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Potential role of oxidative stress in the pathogenesis of diabetic bladder dysfunction

Abstract

Diabetes mellitus is a chronic metabolic disease, posing a considerable threat to global public health. Treating systemic comorbidities has been one of the greatest clinical challenges in the management of diabetes. Diabetic bladder dysfunction, characterized by detrusor overactivity during the early stage of the disease and detrusor underactivity during the late stage, is a common urological complication of diabetes. Oxidative stress is thought to trigger hyperglycaemia-dependent tissue damage in multiple organs; thus, a growing body of literature has suggested a possible link between functional changes in urothelium, muscle and the corresponding innervations. Improved understanding of the mechanisms of oxidative stress could lead to the development of novel therapeutics to restore the redox equilibrium and scavenge excessive free radicals to normalize bladder function in patients with diabetes.

Key points

  • Oxidative stress, characterized by either excessive reactive oxygen species production or disturbed antioxidant regulation, occurs in biological systems in normal and pathological conditions.

  • In physiological conditions, reactive oxygen species have a crucial role in cell metabolism, proliferation, differentiation, inflammatory response and preservation of mitochondrial function.

  • The balance between oxidants and antioxidants is maintained through several intertwined mechanisms that could be vulnerable to hyperglycaemia, leading to dysregulated oxidative stress and diabetic complications.

  • Diabetic bladder dysfunction (DBD) can manifest with functional abnormalities varying over time, characterized by a sensory urgency in the early stage, and an impaired sensation of bladder fullness and impaired bladder emptying in the late stage.

  • Hyperglycaemia-induced oxidative stress leading to DBD might also be responsible for impaired contractility of smooth muscle, altered sensory response of urothelium, and slowed conduction of lower urinary tract innervation.

  • In-depth research on dysregulated mechanisms of oxidative stress will facilitate the development of novel treatments targeting deficient pathways to mitigate DBD.

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Fig. 1: Reactive oxygen species production and clearance.
Fig. 2: Crosstalk between reactive oxygen species and signalling pathways under physiological conditions.
Fig. 3: Regulation of oxidative and antioxidative response.
Fig. 4: Potential mechanisms of hyperglycaemia-induced excessive reactive oxygen species production.
Fig. 5: Pathophysiological changes induced by oxidative stress during diabetic bladder dysfunction.

References

  1. American Diabetes Association. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2019. Diabetes Care 42, S13–S28 (2019).

    Google Scholar 

  2. Shamseddeen, H., Getty, J. Z., Hamdallah, I. N. & Ali, M. R. Epidemiology and economic impact of obesity and type 2 diabetes. Surg. Clin. North. Am. 91, 1163–1172 (2011).

    PubMed  Google Scholar 

  3. Saeedi, P. et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res. Clin. Pract. 157, 107843 (2019).

    PubMed  Google Scholar 

  4. DeFronzo, R. A. et al. Type 2 diabetes mellitus. Nat. Rev. Dis. Prim. 1, 15019 (2015).

    PubMed  Google Scholar 

  5. Huang, E. S. Management of diabetes mellitus in older people with comorbidities. BMJ 353, i2200 (2016).

    PubMed  PubMed Central  Google Scholar 

  6. Yang, W. et al. Estimating costs of diabetes complications in people <65 years in the U.S. using panel data. J. Diabetes Complicat. 34, 107735 (2020).

    Google Scholar 

  7. Giri, B. et al. Chronic hyperglycemia mediated physiological alteration and metabolic distortion leads to organ dysfunction, infection, cancer progression and other pathophysiological consequences: an update on glucose toxicity. Biomed. Pharmacother. 107, 306–328 (2018).

    CAS  PubMed  Google Scholar 

  8. Paul, S., Ali, A. & Katare, R. Molecular complexities underlying the vascular complications of diabetes mellitus — a comprehensive review. J. Diabetes Complicat. 34, 107613 (2020).

    Google Scholar 

  9. Gomez, C. S., Kanagarajah, P. & Gousse, A. E. Bladder dysfunction in patients with diabetes. Curr. Urol. Rep. 12, 419–426 (2011).

    PubMed  Google Scholar 

  10. Gandhi, J., Dagur, G., Warren, K., Smith, N. L. & Khan, S. A. Genitourinary complications of diabetes mellitus: an overview of pathogenesis, evaluation, and management. Curr. Diabetes Rev. 13, 498–518 (2017).

    PubMed  Google Scholar 

  11. Brown, J. S. et al. Urologic complications of diabetes. Diabetes Care 28, 177–185 (2005).

    PubMed  Google Scholar 

  12. Arrellano-Valdez, F., Urrutia-Osorio, M., Arroyo, C. & Soto-Vega, E. A comprehensive review of urologic complications in patients with diabetes. SpringerPlus 3, 549 (2014).

    PubMed  PubMed Central  Google Scholar 

  13. Nirmal, J. et al. Functional and molecular characterization of hyposensitive underactive bladder tissue and urine in streptozotocin-induced diabetic rat. PLoS One 9, e102644 (2014).

    PubMed  PubMed Central  Google Scholar 

  14. Palleschi, G. et al. Overactive bladder in diabetes mellitus patients: a questionnaire-based observational investigation. World J. Urol. 32, 1021–1025 (2014).

    PubMed  Google Scholar 

  15. Fayyad, A. M., Hill, S. R. & Jones, G. Prevalence and risk factors for bothersome lower urinary tract symptoms in women with diabetes mellitus from hospital-based diabetes clinic. Int. Urogynecol. J. Pelvic Floor. Dysfunct. 20, 1339–1344 (2009).

    PubMed  Google Scholar 

  16. Qaseem, A. et al. Hemoglobin A1c targets for glycemic control with pharmacologic therapy for nonpregnant adults with type 2 diabetes mellitus: a guidance statement update from the American College of Physicians. Ann. Intern. Med. 168, 569–576 (2018).

    PubMed  Google Scholar 

  17. Wang, R., Lefevre, R., Hacker, M. R. & Golen, T. H. Diabetes, glycemic control, and urinary incontinence in women. Female Pelvic Med. Reconstr. Surg. 21, 293–297 (2015).

    PubMed  PubMed Central  Google Scholar 

  18. Liu, N. et al. Relationship between blood glucose and hemoglobin A1c Levels and urinary incontinence in women. Int. J. Gen. Med. 14, 4105–4116 (2021).

    PubMed  PubMed Central  Google Scholar 

  19. Gulur, D. M., Mevcha, A. M. & Drake, M. J. Nocturia as a manifestation of systemic disease. BJU Int. 107, 702–713 (2011).

    PubMed  Google Scholar 

  20. Yoshimura, N., Chancellor, M. B., Andersson, K. E. & Christ, G. J. Recent advances in understanding the biology of diabetes-associated bladder complications and novel therapy. BJU Int. 95, 733–738 (2005).

    PubMed  Google Scholar 

  21. Fedele, D. Therapy insight: sexual and bladder dysfunction associated with diabetes mellitus. Nat. Clin. Pract. Urol. 2, 282–290 (2005). quiz 309.

    PubMed  Google Scholar 

  22. Fowler, C. J., Griffiths, D. & de Groat, W. C. The neural control of micturition. Nat. Rev. Neurosci. 9, 453–466 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Lightner, D. J., Gomelsky, A., Souter, L. & Vasavada, S. P. Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline amendment 2019. J. Urol. 202, 558–563 (2019).

    PubMed  Google Scholar 

  24. Lee, W. C., Wu, C. C., Wu, H. P. & Tai, T. Y. Lower urinary tract symptoms and uroflowmetry in women with type 2 diabetes mellitus with and without bladder dysfunction. Urology 69, 685–690 (2007).

    PubMed  Google Scholar 

  25. Frimodt-Moller, C. Diabetic cystopathy. A review of the urodynamic and clinical features of neurogenic bladder dysfunction in diabetes mellitus. Dan. Med. Bull. 25, 49–60 (1978).

    CAS  PubMed  Google Scholar 

  26. Kaplan, S. A., Te, A. E. & Blaivas, J. G. Urodynamic findings in patients with diabetic cystopathy. J. Urol. 153, 342–344 (1995).

    CAS  PubMed  Google Scholar 

  27. Harding, C. K. et al. EAU guidelines on management of non-neurogenic female lower urinary tract symptoms (LUTS). (EAU, 2021).

  28. Abraham, N. & Goldman, H. B. An update on the pharmacotherapy for lower urinary tract dysfunction. Expert. Opin. Pharmacother. 16, 79–93 (2015).

    CAS  PubMed  Google Scholar 

  29. Kuo, Y.-C. & Kuo, H.-C. Botulinum toxin injection for lower urinary tract dysfunction. Int. J. Urol. 20, 40–55 (2012).

    PubMed  Google Scholar 

  30. Bartley, J., Gilleran, J. & Peters, K. Neuromodulation for overactive bladder. Nat. Rev. Urol. 10, 513–521 (2013).

    CAS  PubMed  Google Scholar 

  31. Chancellor, M. B. & Kaufman, J. Case for pharmacotherapy development for underactive bladder. Urology 72, 966–967 (2008).

    PubMed  Google Scholar 

  32. Osman, N. I. & Chapple, C. R. Are there pharmacotherapeutic options for underactive bladder? Eur. Urol. Focus. 4, 6–7 (2018).

    PubMed  Google Scholar 

  33. Barendrecht, M. M., Oelke, M., Laguna, M. P. & Michel, M. C. Is the use of parasympathomimetics for treating an underactive urinary bladder evidence-based? BJU Int. 99, 749–752 (2007).

    CAS  PubMed  Google Scholar 

  34. Yuan, Z., Tang, Z., He, C. & Tang, W. Diabetic cystopathy: a review. J. Diabetes 7, 442–447 (2015).

    PubMed  Google Scholar 

  35. Andersson, K. E. Oxidative stress and its possible relation to lower urinary tract functional pathology. BJU Int. 121, 527–533 (2018).

    PubMed  Google Scholar 

  36. Pizzino, G. et al. Oxidative stress: harms and benefits for human health. Oxid. Med. Cell. Longev. 2017, 8416763 (2017).

    PubMed  PubMed Central  Google Scholar 

  37. Lushchak, V. I. Free radicals, reactive oxygen species, oxidative stress and its classification. Chem. Biol. Interact. 224, 164–175 (2014).

    CAS  PubMed  Google Scholar 

  38. Sies, H. Oxidative stress: a concept in redox biology and medicine. Redox Biol. 4, 180–183 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Zuo, L., Zhou, T., Pannell, B. K., Ziegler, A. C. & Best, T. M. Biological and physiological role of reactive oxygen species-the good, the bad and the ugly. Acta Physiol. 214, 329–348 (2015).

    CAS  Google Scholar 

  40. Zhang, L. et al. Biochemical basis and metabolic interplay of redox regulation. Redox Biol. 26, 101284 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Brand, M. D. The sites and topology of mitochondrial superoxide production. Exp. Gerontol. 45, 466–472 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Roberge, S. et al. TNF-α-mediated caspase-8 activation induces ROS production and TRPM2 activation in adult ventricular myocytes. Cardiovasc. Res. 103, 90–99 (2014).

    CAS  PubMed  Google Scholar 

  43. Clauzure, M. et al. Disruption of interleukin-1β autocrine signaling rescues complex I activity and improves ROS levels in immortalized epithelial cells with impaired cystic fibrosis transmembrane conductance regulator (CFTR) function. PLoS One 9, e99257 (2014).

    PubMed  PubMed Central  Google Scholar 

  44. Sundaresan, M., Yu, Z. X., Ferrans, V. J., Irani, K. & Finkel, T. Requirement for generation of H2O2 for platelet-derived growth factor signal transduction. Science 270, 296–299 (1995).

    CAS  PubMed  Google Scholar 

  45. Woo, C. H. et al. Tumor necrosis factor-α generates reactive oxygen species via a cytosolic phospholipase A2-linked cascade. J. Biol. Chem. 275, 32357–32362 (2000).

    CAS  PubMed  Google Scholar 

  46. Amir Aslani, B. & Ghobadi, S. Studies on oxidants and antioxidants with a brief glance at their relevance to the immune system. Life Sci. 146, 163–173 (2016).

    CAS  PubMed  Google Scholar 

  47. He, L. et al. Antioxidants maintain cellular redox homeostasis by elimination of reactive oxygen species. Cell. Physiol. Biochem. 44, 532–553 (2017).

    PubMed  Google Scholar 

  48. Yoshioka, J. Thioredoxin superfamily and its effects on cardiac physiology and pathology. Compr. Physiol. 5, 513–530 (2015).

    PubMed  Google Scholar 

  49. Benhar, M. Roles of mammalian glutathione peroxidase and thioredoxin reductase enzymes in the cellular response to nitrosative stress. Free Radic. Biol. Med. 127, 160–164 (2018).

    CAS  PubMed  Google Scholar 

  50. Arevalo, J. A. & Vazquez-Medina, J. P. The role of peroxiredoxin 6 in cell signaling. Antioxidants https://doi.org/10.3390/antiox7120172 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Ledgerwood, E. C., Marshall, J. W. & Weijman, J. F. The role of peroxiredoxin 1 in redox sensing and transducing. Arch. Biochem. Biophys. 617, 60–67 (2017).

    CAS  PubMed  Google Scholar 

  52. Huang, J. Q., Zhou, J. C., Wu, Y. Y., Ren, F. Z. & Lei, X. G. Role of glutathione peroxidase 1 in glucose and lipid metabolism-related diseases. Free Radic. Biol. Med. 127, 108–115 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Gervasoni, B. D., Khairallah, G. N., O’Hair, R. A. & Wille, U. The role of peroxyl radicals in polyester degradation — a mass spectrometric product and kinetic study using the distonic radical ion approach. Phys. Chem. Chem. Phys. 17, 9212–9221 (2015).

    CAS  PubMed  Google Scholar 

  54. Kanti Das, T., Wati, M. R. & Fatima-Shad, K. Oxidative stress gated by Fenton and Haber Weiss reactions and its association with Alzheimer’s disease. Arch. Neurosci. https://doi.org/10.5812/archneurosci.20078 (2014).

    Article  Google Scholar 

  55. Janciauskiene, S. The beneficial effects of antioxidants in health and diseases. Chronic Obstr. Pulm. Dis. 7, 182–202 (2020).

    PubMed  PubMed Central  Google Scholar 

  56. Schieber, M. & Chandel, N. S. ROS function in redox signaling and oxidative stress. Curr. Biol. 24, R453–R462 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Zhang, J. et al. ROS and ROS-mediated cellular signaling. Oxid. Med. Cell. Longev. 2016, 4350965 (2016).

    PubMed  PubMed Central  Google Scholar 

  58. Morgan, M. J. & Liu, Z. G. Crosstalk of reactive oxygen species and NF-κB signaling. Cell Res. 21, 103–115 (2011).

    CAS  PubMed  Google Scholar 

  59. Navarro-Yepes, J. et al. Oxidative stress, redox signaling, and autophagy: cell death versus survival. Antioxid. Redox Signal. 21, 66–85 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Zmijewski, J. W. et al. Exposure to hydrogen peroxide induces oxidation and activation of AMP-activated protein kinase. J. Biol. Chem. 285, 33154–33164 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Tang, J. Y. et al. Oxidative stress-modulating drugs have preferential anticancer effects — involving the regulation of apoptosis, DNA damage, endoplasmic reticulum stress, autophagy, metabolism, and migration. Semin. Cancer Biol. 58, 109–117 (2019).

    CAS  PubMed  Google Scholar 

  62. Newsholme, P., Cruzat, V. F., Keane, K. N., Carlessi, R. & de Bittencourt, P. I. Jr. Molecular mechanisms of ROS production and oxidative stress in diabetes. Biochem. J. 473, 4527–4550 (2016).

    CAS  PubMed  Google Scholar 

  63. Volpe, C. M. O., Villar-Delfino, P. H., Dos Anjos, P. M. F. & Nogueira-Machado, J. A. Cellular death, reactive oxygen species (ROS) and diabetic complications. Cell death Dis. 9, 119 (2018).

    PubMed  PubMed Central  Google Scholar 

  64. Ye, J. et al. The role of autophagy in pro-inflammatory responses of microglia activation via mitochondrial reactive oxygen species in vitro. J. Neurochem. 142, 215–230 (2017).

    CAS  PubMed  Google Scholar 

  65. Cairns, R. A., Harris, I. S. & Mak, T. W. Regulation of cancer cell metabolism. Nat. Rev. Cancer 11, 85–95 (2011).

    CAS  PubMed  Google Scholar 

  66. Moloney, J. N. & Cotter, T. G. ROS signalling in the biology of cancer. Semin. Cell Dev. Biol. 80, 50–64 (2018).

    CAS  PubMed  Google Scholar 

  67. Chavda, V. et al. Molecular mechanisms of oxidative stress in stroke and cancer. Brain Disord. 5, 100029 (2021).

    Google Scholar 

  68. Dizdaroglu, M. & Jaruga, P. Mechanisms of free radical-induced damage to DNA. Free Radic. Res. 46, 382–419 (2012).

    CAS  PubMed  Google Scholar 

  69. Pravalika, K. et al. Myeloperoxidase and neurological disorder: a crosstalk. ACS Chem. Neurosci. 9, 421–430 (2018).

    CAS  PubMed  Google Scholar 

  70. Liu, C. et al. Sulforaphane ameliorates bladder dysfunction through activation of the Nrf2-ARE pathway in a rat model of partial bladder outlet obstruction. Oxid. Med. Cell. Longev. 2016, 7598294 (2016).

    PubMed  PubMed Central  Google Scholar 

  71. Ener, K. et al. Evaluation of oxidative stress status and antioxidant capacity in patients with painful bladder syndrome/interstitial cystitis: preliminary results of a randomised study. Int. Urol. Nephrol. 47, 1297–1302 (2015).

    CAS  PubMed  Google Scholar 

  72. Ma, Q. Role of Nrf2 in oxidative stress and toxicity. Annu. Rev. Pharmacol. Toxicol. 53, 401–426 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Tonelli, C., Chio, I. I. C. & Tuveson, D. A. Transcriptional regulation by Nrf2. Antioxid. Redox Signal. 29, 1727–1745 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Suzuki, T. & Yamamoto, M. Molecular basis of the Keap1-Nrf2 system. Free Radic. Biol. Med. 88, 93–100 (2015).

    CAS  PubMed  Google Scholar 

  75. Tebay, L. E. et al. Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease. Free Radic. Biol. Med. 88, 108–146 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Raghunath, A. et al. Antioxidant response elements: discovery, classes, regulation and potential applications. Redox Biol. 17, 297–314 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Zhang, H., Davies, K. J. A. & Forman, H. J. Oxidative stress response and Nrf2 signaling in aging. Free Radic. Biol. Med. 88, 314–336 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Chung, S. S., Ho, E. C., Lam, K. S. & Chung, S. K. Contribution of polyol pathway to diabetes-induced oxidative stress. J. Am. Soc. Nephrol. 14, S233–S236 (2003).

    CAS  PubMed  Google Scholar 

  79. Obrosova, I. G. Increased sorbitol pathway activity generates oxidative stress in tissue sites for diabetic complications. Antioxid. Redox Signal. 7, 1543–1552 (2005).

    CAS  PubMed  Google Scholar 

  80. Gabbay, K. H. The sorbitol pathway and the complications of diabetes. N. Engl. J. Med. 288, 831–836 (1973).

    CAS  PubMed  Google Scholar 

  81. Ighodaro, O. M. Molecular pathways associated with oxidative stress in diabetes mellitus. Biomed. Pharmacother. 108, 656–662 (2018).

    CAS  PubMed  Google Scholar 

  82. Wu, J., Jin, Z., Zheng, H. & Yan, L. J. Sources and implications of NADH/NAD+ redox imbalance in diabetes and its complications. Diabetes Metab. Syndr. Obes. 9, 145–153 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Bertero, E. & Maack, C. Calcium signaling and reactive oxygen species in mitochondria. Circ. Res. 122, 1460–1478 (2018).

    CAS  PubMed  Google Scholar 

  84. Gordeeva, A. V., Zvyagilskaya, R. A. & Labas, Y. A. Cross-talk between reactive oxygen species and calcium in living cells. Biochemistry 68, 1077–1080 (2003).

    CAS  PubMed  Google Scholar 

  85. Adam-Vizi, V. & Starkov, A. A. Calcium and mitochondrial reactive oxygen species generation: how to read the facts. J. Alzheimers Dis. 20 (Suppl 2), S413–S426 (2010).

    PubMed  PubMed Central  Google Scholar 

  86. Kim, A. N., Jeon, W. K., Lee, J. J. & Kim, B. C. Up-regulation of heme oxygenase-1 expression through CaMKII-ERK1/2-Nrf2 signaling mediates the anti-inflammatory effect of bisdemethoxycurcumin in LPS-stimulated macrophages. Free Radic. Biol. Med. 49, 323–331 (2010).

    CAS  PubMed  Google Scholar 

  87. Batoko, H., Veljanovski, V. & Jurkiewicz, P. Enigmatic translocator protein (TSPO) and cellular stress regulation. Trends Biochem. Sci. 40, 497–503 (2015).

    CAS  PubMed  Google Scholar 

  88. Ilkan, Z. & Akar, F. G. The mitochondrial translocator protein and the emerging link between oxidative stress and arrhythmias in the diabetic heart. Front. Physiol. 9, 1518 (2018).

    PubMed  PubMed Central  Google Scholar 

  89. Zorov, D. B., Filburn, C. R., Klotz, L. O., Zweier, J. L. & Sollott, S. J. Reactive oxygen species (ROS)-induced ROS release: a new phenomenon accompanying induction of the mitochondrial permeability transition in cardiac myocytes. J. Exp. Med. 192, 1001–1014 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Gliozzi, M. et al. Role of TSPO/VDAC1 upregulation and matrix metalloproteinase-2 localization in the dysfunctional myocardium of hyperglycaemic rats. Int. J. Mol. Sci. https://doi.org/10.3390/ijms21207432 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Giatti, S. et al. Neuroprotective effects of a ligand of translocator protein-18 kDa (Ro5-4864) in experimental diabetic neuropathy. Neuroscience 164, 520–529 (2009).

    CAS  PubMed  Google Scholar 

  92. Schwartz, S. S. et al. A unified pathophysiological construct of diabetes and its complications. Trends Endocrinol. Metab. 28, 645–655 (2017).

    CAS  PubMed  Google Scholar 

  93. Kang, Q. & Yang, C. Oxidative stress and diabetic retinopathy: molecular mechanisms, pathogenetic role and therapeutic implications. Redox Biol. 37, 101799 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Giacco, F. & Brownlee, M. Oxidative stress and diabetic complications. Circ. Res. 107, 1058–1070 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Turkmen, K. Inflammation, oxidative stress, apoptosis, and autophagy in diabetes mellitus and diabetic kidney disease: the four horsemen of the apocalypse. Int. Urol. Nephrol. 49, 837–844 (2017).

    CAS  PubMed  Google Scholar 

  96. Dewanjee, S. et al. Molecular mechanism of diabetic neuropathy and its pharmacotherapeutic targets. Eur. J. Pharmacol. 833, 472–523 (2018).

    CAS  PubMed  Google Scholar 

  97. Singh, R., Kishore, L. & Kaur, N. Diabetic peripheral neuropathy: current perspective and future directions. Pharmacol. Res. 80, 21–35 (2014).

    CAS  PubMed  Google Scholar 

  98. Tang, W. H., Martin, K. A. & Hwa, J. Aldose reductase, oxidative stress, and diabetic mellitus. Front. Pharmacol. 3, 87 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Berthiaume, J. M., Kurdys, J. G., Muntean, D. M. & Rosca, M. G. Mitochondrial NAD+/NADH redox state and diabetic cardiomyopathy. Antioxid. Redox Signal. 30, 375–398 (2019).

    CAS  PubMed  Google Scholar 

  100. Andres-Hernando, A., Johnson, R. J. & Lanaspa, M. A. Endogenous fructose production: what do we know and how relevant is it. Curr. Opin. Clin. Nutr. Metab. Care 22, 289–294 (2019).

    PubMed  PubMed Central  Google Scholar 

  101. DiNicolantonio, J. J., O’Keefe, J. H. & Lucan, S. C. Added fructose: a principal driver of type 2 diabetes mellitus and its consequences. Mayo Clin. Proc. 90, 372–381 (2015).

    CAS  PubMed  Google Scholar 

  102. Basciano, H., Federico, L. & Adeli, K. Fructose, insulin resistance, and metabolic dyslipidemia. Nutr. Metab. 2, 5 (2005).

    Google Scholar 

  103. Akamine, T., Kusunose, N., Matsunaga, N., Koyanagi, S. & Ohdo, S. Accumulation of sorbitol in the sciatic nerve modulates circadian properties of diabetes-induced neuropathic pain hypersensitivity in a diabetic mouse model. Biochem. Biophys. Res. Commun. 503, 181–187 (2018).

    CAS  PubMed  Google Scholar 

  104. Wu, M. Y., Yiang, G. T., Lai, T. T. & Li, C. J. The oxidative stress and mitochondrial dysfunction during the pathogenesis of diabetic retinopathy. Oxid. Med. Cell. Longev. 2018, 3420187 (2018).

    PubMed  PubMed Central  Google Scholar 

  105. Lorenzi, M. The polyol pathway as a mechanism for diabetic retinopathy: attractive, elusive, and resilient. Exp. Diabetes Res. 2007, 61038 (2007).

    PubMed  PubMed Central  Google Scholar 

  106. Hashimoto, Y. et al. Polyol pathway and diabetic nephropathy revisited: early tubular cell changes and glomerulopathy in diabetic mice overexpressing human aldose reductase. J. Diabetes Invest. 2, 111–122 (2011).

    CAS  Google Scholar 

  107. He, J. et al. The aldose reductase inhibitor epalrestat exerts nephritic protection on diabetic nephropathy in db/db mice through metabolic modulation. Acta Pharmacol. Sin. 40, 86–97 (2019).

    CAS  PubMed  Google Scholar 

  108. Ramirez, M. A. & Borja, N. L. Epalrestat: an aldose reductase inhibitor for the treatment of diabetic neuropathy. Pharmacotherapy 28, 646–655 (2008).

    CAS  PubMed  Google Scholar 

  109. Reiser, J. & Altintas, M. M. Podocytes. F1000Res https://doi.org/10.12688/f1000research.7255.1 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Kiyono, Y., Kajiyama, S., Fujiwara, H., Kanegawa, N. & Saji, H. Influence of the polyol pathway on norepinephrine transporter reduction in diabetic cardiac sympathetic nerves: implications for heterogeneous accumulation of MIBG. Eur. J. Nucl. Med. Mol. Imaging 32, 438–442 (2005).

    PubMed  Google Scholar 

  111. D’Souza, D. R. et al. Hyperglycemia regulates RUNX2 activation and cellular wound healing through the aldose reductase polyol pathway. J. Biol. Chem. 284, 17947–17955 (2009).

    PubMed  PubMed Central  Google Scholar 

  112. Cheng, J. T. & Tong, Y. C. Alterations of nerve-growth factor and p75(NTR) expressions in urinary bladder of fructose-fed obese rats. Neurosci. Lett. 441, 25–28 (2008).

    CAS  PubMed  Google Scholar 

  113. Tong, Y. C. & Cheng, J. T. Aldose reductase inhibitor ONO-2235 restores the alterations of bladder nerve growth factor and neurotrophin receptor p75 genetic expression in streptozotocin induced diabetic rats. J. Urol. 178, 2203–2207 (2007).

    CAS  PubMed  Google Scholar 

  114. Hanna-Mitchell, A. T. et al. Impact of diabetes mellitus on bladder uroepithelial cells. Am. J. Physiol. Regul. Integr. Comp. Physiol. 304, R84–R93 (2013).

    CAS  PubMed  Google Scholar 

  115. Mannikarottu, A. S., Changolkar, A. K., Disanto, M. E., Wein, A. J. & Chacko, S. Over expression of smooth muscle thin filament associated proteins in the bladder wall of diabetics. J. Urol. 174, 360–364 (2005).

    CAS  PubMed  Google Scholar 

  116. Changolkar, A. K. et al. Diabetes induced decrease in detrusor smooth muscle force is associated with oxidative stress and overactivity of aldose reductase. J. Urol. 173, 309–313 (2005).

    CAS  PubMed  Google Scholar 

  117. Wang, Y., Deng, G. G. & Davies, K. P. Novel insights into development of diabetic bladder disorder provided by metabolomic analysis of the rat nondiabetic and diabetic detrusor and urothelial layer. Am. J. Physiol. Endocrinol. Metab. 311, E471–E479 (2016).

    PubMed  PubMed Central  Google Scholar 

  118. Nowotny, K., Jung, T., Hohn, A., Weber, D. & Grune, T. Advanced glycation end products and oxidative stress in type 2 diabetes mellitus. Biomolecules 5, 194–222 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Brings, S. et al. Dicarbonyls and advanced glycation end-products in the development of diabetic complications and targets for intervention. Int. J. Mol. Sci. https://doi.org/10.3390/ijms18050984 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Moldogazieva, N. T., Mokhosoev, I. M., Mel’nikova, T. I., Porozov, Y. B. & Terentiev, A. A. Oxidative stress and advanced lipoxidation and glycation end products (ALEs and AGEs) in aging and age-related diseases. Oxid. Med. Cell. Longev. 2019, 3085756 (2019).

    PubMed  PubMed Central  Google Scholar 

  121. Gali, A. et al. Correlation between advanced glycation end-products, lower urinary tract symptoms and bladder dysfunctions in patients with type 2 diabetes mellitus. Low. Urin. Tract. Symptoms 9, 15–20 (2017).

    CAS  PubMed  Google Scholar 

  122. Mancini, V. et al. Is coexistent overactive-underactive bladder (with or without detrusor overactivity and underactivity) a real clinical syndrome? ICI-RS 2019. Neurourol. Urodyn. 39(Suppl 3), S50–S59 (2020).

    PubMed  Google Scholar 

  123. Kanwar, M. & Kowluru, R. A. Role of glyceraldehyde 3-phosphate dehydrogenase in the development and progression of diabetic retinopathy. Diabetes 58, 227–234 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Kizub, I. V., Klymenko, K. I. & Soloviev, A. I. Protein kinase C in enhanced vascular tone in diabetes mellitus. Int. J. Cardiol. 174, 230–242 (2014).

    PubMed  Google Scholar 

  125. Loscalzo, J. The identification of nitric oxide as endothelium-derived relaxing factor. Circulation Res. 113, 100–103 (2013).

    CAS  PubMed  Google Scholar 

  126. Vanhoutte, P. M., Shimokawa, H., Feletou, M. & Tang, E. H. Endothelial dysfunction and vascular disease — a 30th anniversary update. Acta Physiol. 219, 22–96 (2017).

    CAS  Google Scholar 

  127. Nobe, K., Yamazaki, T., Tsumita, N., Hashimoto, T. & Honda, K. Glucose-dependent enhancement of diabetic bladder contraction is associated with a rho kinase-regulated protein kinase C pathway. J. Pharmacol. Exp. Ther. 328, 940–950 (2009).

    CAS  PubMed  Google Scholar 

  128. Baumel-Alterzon, S., Katz, L. S., Brill, G., Garcia-Ocana, A. & Scott, D. K. Nrf2: the master and captain of β cell fate. Trends Endocrinol. Metab. 32, 7–19 (2021).

    CAS  PubMed  Google Scholar 

  129. Tan, Y. et al. Diabetic downregulation of Nrf2 activity via ERK contributes to oxidative stress-induced insulin resistance in cardiac cells in vitro and in vivo. Diabetes 60, 625–633 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Whitmarsh, A. J. Regulation of gene transcription by mitogen-activated protein kinase signaling pathways. Biochim. Biophys. Acta 1773, 1285–1298 (2007).

    CAS  PubMed  Google Scholar 

  131. Vessieres, E. et al. COX-2-derived prostanoids and oxidative stress additionally reduce endothelium-mediated relaxation in old type 2 diabetic rats. PLoS One 8, e68217 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Ganesh Yerra, V., Negi, G., Sharma, S. S. & Kumar, A. Potential therapeutic effects of the simultaneous targeting of the Nrf2 and NF-κB pathways in diabetic neuropathy. Redox Biol. 1, 394–397 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Horn, S. et al. Research resource: a dual proteomic approach identifies regulated islet proteins during beta-cell mass expansion in vivo. Mol. Endocrinol. 30, 133–143 (2016).

    CAS  PubMed  Google Scholar 

  134. Salazar-Petres, E. R. & Sferruzzi-Perri, A. N. Pregnancy-induced changes in beta-cell function: what are the key players? J. Physiol. 600, 1089–1117 (2022).

    CAS  PubMed  Google Scholar 

  135. Yagishita, Y., Uruno, A., Chartoumpekis, D. V., Kensler, T. W. & Yamamoto, M. Nrf2 represses the onset of type 1 diabetes in non-obese diabetic mice. J. Endocrinol. https://doi.org/10.1530/JOE-18-0355 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  136. Kumar, A. et al. Activation of Nrf2 is required for normal and ChREBPα-augmented glucose-stimulated beta-cell proliferation. Diabetes 67, 1561–1575 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Li, L. et al. Luteolin protects against diabetic cardiomyopathy by inhibiting NF-κB-mediated inflammation and activating the Nrf2-mediated antioxidant responses. Phytomedicine 59, 152774 (2019).

    CAS  PubMed  Google Scholar 

  138. Yu, H. et al. Rg1 protects H9C2 cells from high glucose-/palmitate-induced injury via activation of AKT/GSK-3β/Nrf2 pathway. J. Cell. Mol. Med. 24, 8194–8205 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Huang, K., Gao, X. & Wei, W. The crosstalk between Sirt1 and Keap1/Nrf2/ARE anti-oxidative pathway forms a positive feedback loop to inhibit FN and TGF-β1 expressions in rat glomerular mesangial cells. Exp. Cell Res. 361, 63–72 (2017).

    CAS  PubMed  Google Scholar 

  140. Ha, U. S. et al. Protective effect of cyanidin-3-O-beta-D-glucopyranoside fraction from mulberry fruit pigment against oxidative damage in streptozotocin-induced diabetic rat bladder. Neurourol. Urodyn. 32, 493–499 (2013).

    CAS  PubMed  Google Scholar 

  141. Elrashidy, R. A. & Liu, G. Long-term diabetes causes molecular alterations related to fibrosis and apoptosis in rat urinary bladder. Exp. Mol. Pathol. 111, 104304 (2019).

    CAS  PubMed  Google Scholar 

  142. Wang, J. et al. IR-61 improves voiding function via mitochondrial protection in diabetic rats. Front. Pharmacol. 12, 608637 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Cao, N., Gu, B., Gotoh, D. & Yoshimura, N. Time-dependent changes of urethral function in diabetes mellitus: a review. Int. Neurourol. J. 23, 91–99 (2019).

    PubMed  PubMed Central  Google Scholar 

  144. Daneshgari, F., Liu, G., Birder, L., Hanna-Mitchell, A. T. & Chacko, S. Diabetic bladder dysfunction: current translational knowledge. J. Urol. 182, S18–S26 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Brownlee, M. Biochemistry and molecular cell biology of diabetic complications. Nature 414, 813–820 (2001).

    CAS  PubMed  Google Scholar 

  146. Golbidi, S. & Laher, I. Bladder dysfunction in diabetes mellitus. Front. Pharmacol. https://doi.org/10.3389/fphar.2010.00136 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Abler, L. L. & Vezina, C. M. Respiratory physiology & neurobiology links between lower urinary tract symptoms, intermittent hypoxia and diabetes: causes or cures. Respir. Physiol. Neurobiol. https://doi.org/10.1016/j.resp.2017.09.009 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  148. Kirschner-Hermanns, R. et al. Does diabetes mellitus-induced bladder remodeling affect lower urinary tract function? ICI-RS 2011. Neurourol. Urodyn. 31, 359–364 (2012).

    PubMed  Google Scholar 

  149. Daneshgari, F. et al. Temporal differences in bladder dysfunction caused by diabetes, diuresis, and treated diabetes in mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 290, R1728–R1735 (2006).

    CAS  PubMed  Google Scholar 

  150. Daneshgari, F., Liu, G. & Imrey, P. B. Time dependent changes in diabetic cystopathy in rats include compensated and decompensated bladder function. J. Urol. 176, 380–386 (2006).

    PubMed  Google Scholar 

  151. Liu, G., Lin, Y. H., Yamada, Y. & Daneshgari, F. External urethral sphincter activity in diabetic rats. Neurourol. Urodyn. 27, 429–434 (2008).

    PubMed  Google Scholar 

  152. Yono, M., Latifpour, J., Yoshida, M. & Ueda, S. Age-related alterations in the biochemical and functional properties of the bladder in type 2 diabetic GK rats. J. Recept. Signal. Transduct. Res. 25, 147–157 (2005).

    CAS  PubMed  Google Scholar 

  153. Gasbarro, G. et al. Voiding function in obese and type 2 diabetic female rats. Am. J. Physiol. Renal Physiol. 298, F72–F77 (2010).

    CAS  PubMed  Google Scholar 

  154. Kendig, D. M., Ets, H. K. & Moreland, R. S. Effect of type II diabetes on male rat bladder contractility. Am. J. Physiol. Renal Physiol. 310, F909–F922 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Kim, A. K., Hamadani, C., Zeidel, M. L. & Hill, W. G. Urological complications of obesity and diabetes in males and females of three mouse models: temporal manifestations. Am. J. Physiol. Renal Physiol. 318, F160–F174 (2020).

    CAS  PubMed  Google Scholar 

  156. Klee, N. S., Moreland, R. S. & Kendig, D. M. Detrusor contractility to parasympathetic mediators is differentially altered in the compensated and decompensated states of diabetic bladder dysfunction. Am. J. Physiol. Renal Physiol. 317, F388–F398 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Aizawa, N., Homma, Y. & Igawa, Y. Characteristics of lower urinary tract dysfunction and bladder afferent nerve properties in type 2 diabetic Goto-Kakizaki rats. J. Urol. 189, 1580–1587 (2013).

    PubMed  Google Scholar 

  158. Sullivan, C. J. et al. Microarray analysis reveals novel gene expression changes associated with erectile dysfunction in diabetic rats. Physiol. Genomics 23, 192–205 (2005).

    CAS  PubMed  Google Scholar 

  159. Hipp, J. D. et al. Using gene chips to identify organ-specific, smooth muscle responses to experimental diabetes: potential applications to urological diseases. BJU Int. 99, 418–430 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Kanika, N. D. et al. Oxidative stress status accompanying diabetic bladder cystopathy results in the activation of protein degradation pathways. BJU Int. 107, 1676–1684 (2011).

    CAS  PubMed  Google Scholar 

  161. Yohannes, E., Chang, J., Christ, G. J., Davies, K. P. & Chance, M. R. Proteomics analysis identifies molecular targets related to diabetes mellitus-associated bladder dysfunction. Mol. Cell Proteom. 7, 1270–1285 (2008).

    CAS  Google Scholar 

  162. Tomechko, S. E. et al. Tissue specific dysregulated protein subnetworks in type 2 diabetic bladder urothelium and detrusor muscle. Mol. Cell Proteom. 14, 635–645 (2015).

    CAS  Google Scholar 

  163. Poladia, D. P. & Bauer, J. A. Oxidant driven signaling pathways during diabetes: role of Rac1 and modulation of protein kinase activity in mouse urinary bladder. Biochimie 86, 543–551 (2004).

    CAS  PubMed  Google Scholar 

  164. Li, W. J. & Oh, S. J. Diabetic cystopathy is associated with PARP/JNK/mitochondrial apoptotic pathway-mediated bladder apoptosis. Neurourol. Urodyn. 29, 1332–1337 (2010).

    CAS  PubMed  Google Scholar 

  165. Kaneto, H. et al. Oxidative stress and the JNK pathway are involved in the development of type 1 and type 2 diabetes. Curr. Mol. Med. 7, 674–686 (2007).

    CAS  PubMed  Google Scholar 

  166. Beshay, E. & Carrier, S. Oxidative stress plays a role in diabetes-induced bladder dysfunction in a rat model. Urology 64, 1062–1067 (2004).

    PubMed  Google Scholar 

  167. Elrashidy, R. A. et al. Smooth muscle-specific deletion of MnSOD exacerbates diabetes-induced bladder dysfunction in mice. Am. J. Physiol. Renal Physiol. 317, F906–F912 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Lee, W. C., Chien, C. T., Yu, H. J. & Lee, S. W. Bladder dysfunction in rats with metabolic syndrome induced by long-term fructose feeding. J. Urol. 179, 2470–2476 (2008).

    PubMed  Google Scholar 

  169. Birder, L. A. et al. How does the urothelium affect bladder function in health and disease? ICI-RS 2011. Neurourol. Urodyn. 31, 293–299 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Merrill, L., Gonzalez, E. J., Girard, B. M. & Vizzard, M. A. Receptors, channels, and signalling in the urothelial sensory system in the bladder. Nat. Rev. Urol. 13, 193–204 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Birder, L. A. & de Groat, W. C. Mechanisms of disease: involvement of the urothelium in bladder dysfunction. Nat. Clin. Pract. Urol. 4, 46–54 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Dalghi, M. G., Montalbetti, N., Carattino, M. D. & Apodaca, G. The urothelium: life in a liquid environment. Physiol. Rev. 100, 1621–1705 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Hurst, R. E. et al. In the absence of overt urothelial damage, chondroitinase ABC digestion of the GAG layer increases bladder permeability in ovariectomized female rats. Am. J. Physiol. Renal Physiol. 310, F1074–F1080 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Coccheri, S. Approaches to prevention of cardiovascular complications and events in diabetes mellitus. Drugs 67, 997–1026 (2007).

    CAS  PubMed  Google Scholar 

  175. Pinna, C., Bolego, C. & Puglisi, L. Effect of substance P and capsaicin on urinary bladder of diabetic rats and the role of the epithelium. Eur. J. Pharmacol. 271, 151–158 (1994).

    CAS  PubMed  Google Scholar 

  176. Pinna, C., Caratozzolo, O. & Puglisi, L. A possible role for urinary bladder epithelium in bradykinin-induced contraction in diabetic rats. Eur. J. Pharmacol. 214, 143–148 (1992).

    CAS  PubMed  Google Scholar 

  177. Pinna, C., Zanardo, R. & Puglisi, L. Prostaglandin-release impairment in the bladder epithelium of streptozotocin-induced diabetic rats. Eur. J. Pharmacol. 388, 267–273 (2000).

    CAS  PubMed  Google Scholar 

  178. Tong, Y. C., Cheng, J. T. & Hsu, C. T. Alterations of M2-muscarinic receptor protein and mRNA expression in the urothelium and muscle layer of the streptozotocin-induced diabetic rat urinary bladder. Neurosci. Lett. 406, 216–221 (2006).

    CAS  PubMed  Google Scholar 

  179. Cheng, J. T., Yu, B. C. & Tong, Y. C. Changes of M3-muscarinic receptor protein and mRNA expressions in the bladder urothelium and muscle layer of streptozotocin-induced diabetic rats. Neurosci. Lett. 423, 1–5 (2007).

    CAS  PubMed  Google Scholar 

  180. Wang, C. C. & Kuo, H. C. Urothelial Dysfunction and chronic inflammation in diabetic patients with overactive bladder. Low. Urin. Tract. Symptoms 9, 151–156 (2017).

    CAS  PubMed  Google Scholar 

  181. Poladia, D. P. & Bauer, J. A. Early cell-specific changes in nitric oxide synthases, reactive nitrogen species formation, and ubiquitinylation during diabetes-related bladder remodeling. Diabetes Metab. Res. Rev. 19, 313–319 (2003).

    CAS  PubMed  Google Scholar 

  182. Deli, G., Bosnyak, E., Pusch, G., Komoly, S. & Feher, G. Diabetic neuropathies: diagnosis and management. Neuroendocrinology 98, 267–280 (2013).

    CAS  PubMed  Google Scholar 

  183. Burakgazi, A. Z., Alsowaity, B., Burakgazi, Z. A., Unal, D. & Kelly, J. J. Bladder dysfunction in peripheral neuropathies. Muscle Nerve 45, 2–8 (2012).

    PubMed  Google Scholar 

  184. Van Poppel, H., Stessens, R., Van Damme, B., Carton, H. & Baert, L. Diabetic cystopathy: neuropathological examination of urinary bladder biopsies. Eur. Urol. 15, 128–131 (1988).

    PubMed  Google Scholar 

  185. Lee, W. C., Wu, H. P., Tai, T. Y., Yu, H. J. & Chiang, P. H. Investigation of urodynamic characteristics and bladder sensory function in the early stages of diabetic bladder dysfunction in women with type 2 diabetes. J. Urol. 181, 198–203 (2009).

    PubMed  Google Scholar 

  186. Mitsui, T. et al. Vesicourethral function in diabetic patients: association of abnormal nerve conduction velocity with vesicourethral dysfunction. Neurourol. Urodyn. 18, 639–645 (1999).

    CAS  PubMed  Google Scholar 

  187. Melman, A. et al. Longitudinal studies of time-dependent changes in both bladder and erectile function after streptozotocin-induced diabetes in Fischer 344 male rats. BJU Int. 104, 1292–1300 (2009).

    PubMed  Google Scholar 

  188. Liu, G. & Daneshgari, F. Alterations in neurogenically mediated contractile responses of urinary bladder in rats with diabetes. Am. J. Physiol. Renal Physiol. 288, F1220–F1226 (2005).

    CAS  PubMed  Google Scholar 

  189. Blaha, I. et al. Bladder dysfunction in an obese Zucker rat: the role of TRPA1 channels, oxidative stress, and hydrogen sulfide. Oxid. Med. Cell. Longev. 2019, 5641645 (2019).

    PubMed  PubMed Central  Google Scholar 

  190. Ochodnicky, P., Cruz, C. D., Yoshimura, N. & Michel, M. C. Nerve growth factor in bladder dysfunction: contributing factor, biomarker, and therapeutic target. Neurourol. Urodyn. 30, 1227–1241 (2011).

    CAS  PubMed  Google Scholar 

  191. Song, Q. X., Chermansky, C. J., Birder, L. A., Li, L. & Damaser, M. S. Brain-derived neurotrophic factor in urinary continence and incontinence. Nat. Rev. Urol. 11, 579–588 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Steinbacher, B. C. Jr & Nadelhaft, I. Increased levels of nerve growth factor in the urinary bladder and hypertrophy of dorsal root ganglion neurons in the diabetic rat. Brain Res. 782, 255–260 (1998).

    CAS  PubMed  Google Scholar 

  193. Sasaki, K. et al. Diabetic cystopathy correlates with a long-term decrease in nerve growth factor levels in the bladder and lumbosacral dorsal root Ganglia. J. Urol. 168, 1259–1264 (2002).

    PubMed  Google Scholar 

  194. Tong, Y. C. & Cheng, J. T. Changes in bladder nerve-growth factor and p75 genetic expression in streptozotocin-induced diabetic rats. BJU Int. 96, 1392–1396 (2005).

    CAS  PubMed  Google Scholar 

  195. Nykjaer, A. & Willnow, T. E. Sortilin: a receptor to regulate neuronal viability and function. Trends Neurosci. 35, 261–270 (2012).

    CAS  PubMed  Google Scholar 

  196. Barker, P. A. p75NTR is positively promiscuous: novel partners and new insights. Neuron 42, 529–533 (2004).

    CAS  PubMed  Google Scholar 

  197. Mossa, A. H. et al. Antagonism of proNGF or its receptor p75NTR reverses remodelling and improves bladder function in a mouse model of diabetic voiding dysfunction. Diabetologia 63, 1932–1946 (2020).

    CAS  PubMed  Google Scholar 

  198. Goins, W. F. et al. Herpes simplex virus mediated nerve growth factor expression in bladder and afferent neurons: potential treatment for diabetic bladder dysfunction. J. Urol. 165, 1748–1754 (2001).

    CAS  PubMed  Google Scholar 

  199. Goss, J. R. et al. Herpes simplex-mediated gene transfer of nerve growth factor protects against peripheral neuropathy in streptozotocin-induced diabetes in the mouse. Diabetes 51, 2227–2232 (2002).

    CAS  PubMed  Google Scholar 

  200. Sasaki, K. et al. Gene therapy using replication-defective herpes simplex virus vectors expressing nerve growth factor in a rat model of diabetic cystopathy. Diabetes 53, 2723–2730 (2004).

    CAS  PubMed  Google Scholar 

  201. Azadzoi, K. M., Yalla, S. V. & Siroky, M. B. Oxidative stress and neurodegeneration in the ischemic overactive bladder. J. Urol. 178, 710–715 (2007).

    CAS  PubMed  Google Scholar 

  202. Li, B., Lang, N. & Cheng, Z. F. Serum levels of brain-derived neurotrophic factor are associated with diabetes risk, complications, and obesity: a cohort study from Chinese patients with type 2 diabetes. Mol. Neurobiol. 53, 5492–5499 (2016).

    CAS  PubMed  Google Scholar 

  203. He, M. & Wang, J. Decreased serum brain-derived neurotrophic factor in Chinese patients with type 2 diabetes mellitus. Acta Biochim. Biophys. Sin. 46, 426–427 (2014).

    PubMed  Google Scholar 

  204. Xue, J. et al. Caffeine improves bladder function in diabetic rats via a neuroprotective effect. Exp. Ther. Med. 21, 501 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Sun, Z. et al. NGF protects against oxygen and glucose deprivation-induced oxidative stress and apoptosis by up-regulation of HO-1 through MEK/ERK pathway. Neurosci. Lett. 641, 8–14 (2017).

    CAS  PubMed  Google Scholar 

  206. Li, R. et al. NGF attenuates high glucose-induced ER stress, preventing Schwann cell apoptosis by activating the PI3K/Akt/GSK3β and ERK1/2 pathways. Neurochem. Res. 42, 3005–3018 (2017).

    CAS  PubMed  Google Scholar 

  207. Qi, G. et al. Neuroprotective action of tea polyphenols on oxidative stress-induced apoptosis through the activation of the TrkB/CREB/BDNF pathway and Keap1/Nrf2 signaling pathway in SH-SY5Y cells and mice brain. Food Funct. 8, 4421–4432 (2017).

    CAS  PubMed  Google Scholar 

  208. Behl, T. & Kotwani, A. Downregulated brain-derived neurotrophic factor-induced oxidative stress in the pathophysiology of diabetic retinopathy. Can. J. Diabetes 41, 241–246 (2017).

    PubMed  Google Scholar 

  209. Yamanaka, M. et al. Protective effect of brain-derived neurotrophic factor on pancreatic islets in obese diabetic mice. Metabolism 55, 1286–1292 (2006).

    CAS  PubMed  Google Scholar 

  210. Tsounapi, P., Honda, M., Hikita, K., Sofikitis, N. & Takenaka, A. Oxidative stress alterations in the bladder of a short-period type 2 diabetes rat model: antioxidant treatment can be beneficial for the bladder. In Vivo 33, 1819–1826 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. Lin, C. F. et al. Sulforaphane improves voiding function via the preserving mitochondrial function in diabetic rats. J. Formos. Med. Assoc. 119, 1422–1430 (2020).

    CAS  PubMed  Google Scholar 

  212. Zhang, B. et al. Grape seed proanthocyanidin extract alleviates urethral dysfunction in diabetic rats through modulating the NO-cGMP pathway. Exp. Ther. Med. 15, 1053–1061 (2018).

    CAS  PubMed  Google Scholar 

  213. Pergola, P. E. et al. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N. Engl. J. Med. 365, 327–336 (2011).

    CAS  PubMed  Google Scholar 

  214. Himmelfarb, J. & Tuttle, K. R. New therapies for diabetic kidney disease. N. Engl. J. Med. 369, 2549–2550 (2013).

    CAS  PubMed  Google Scholar 

  215. Zhang, P. et al. Oxidative stress and diabetes: antioxidative strategies. Front. Med. 14, 583–600 (2020).

    PubMed  Google Scholar 

  216. Hybertson, B. M., Gao, B., Bose, S. K. & McCord, J. M. Oxidative stress in health and disease: the therapeutic potential of Nrf2 activation. Mol. Asp. Med. 32, 234–246 (2011).

    CAS  Google Scholar 

  217. Bouayed, J. & Bohn, T. Exogenous antioxidants — double-edged swords in cellular redox state: health beneficial effects at physiologic doses versus deleterious effects at high doses. Oxid. Med. Cell. Longev. 3, 228–237 (2010).

    PubMed  PubMed Central  Google Scholar 

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All authors researched data for the article. Q.X.S., M.S.D., Y.S. contributed substantially to discussion of the content. All authors wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Glossary

Sensory urgency

Increased perceived bladder sensation during filling, with a low bladder capacity and a short voiding duration.

Daytime frequency

Micturition occurring more frequently during waking hours than previously deemed normal by the patient (defined by the International Urogynecological Association/International Continence Society).

Pressure flow urodynamic testing

Refers to the voiding part during a urodynamic test, in which bladder pressure is measured simultaneously with the urinary flow.

Clean intermittent catheterization

A method of draining the urine out of the bladder using a thin, soft tube, which is removed immediately once the bladder is emptied.

Timed voiding

To void at fixed time intervals, instead of relying on the sensation of bladder fullness.

Double voiding

To pass urine more than once during each void with the purpose of reducing residual volume.

Antioxidant response element

(ARE). Transcription regulators acting with nuclear factor erythroid 2-related factor 2 to restore redox homeostasis and to activate cytoprotection in response to oxidative stress.

Streptozotocin (STZ)-induced rat model

An animal model of type 1 diabetes induced by intravenous injection of streptozotocin to cause pancreatic islet β cell destruction.

International Prostatic Symptom Score

A questionnaire containing seven items to assess the severity of lower urinary tract symptoms in male patients.

Threshold pressure

The pressure recorded just before the onset of voiding during cystometry.

Cystometric contraction pressure

Calculated by subtracting threshold pressure from the maximum pressure recorded during micturition.

Swollen mitochondria

A hallmark of mitochondrial dysfunction and cell death, which can be characterized by the opening of permeability transition pores.

Metabolome

The complete collection of low-molecular weight metabolites, participating in the metabolic reactions to maintain cell physiological functions.

Sortilin

A transmembrane protein that forms a receptor complex with p75 neurotrophin receptor, binding with a precursor of nerve growth factor at the cell surface.

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Song, QX., Sun, Y., Deng, K. et al. Potential role of oxidative stress in the pathogenesis of diabetic bladder dysfunction. Nat Rev Urol 19, 581–596 (2022). https://doi.org/10.1038/s41585-022-00621-1

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