Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Role of perivascular cells in kidney homeostasis, inflammation, repair and fibrosis

Nature Reviews Nephrology volume 19, pages 721–732 (2023)Cite this article

Subjects

Abstract

Perivascular niches in the kidney comprise heterogeneous cell populations, including pericytes and fibroblasts, with distinct functions. These perivascular cells have crucial roles in preserving kidney homeostasis as they maintain microvascular networks by stabilizing the vasculature and regulating capillary constriction. A subset of kidney perivascular cells can also produce and secrete erythropoietin; this ability can be enhanced with hypoxia-inducible factor-prolyl hydroxylase inhibitors, which are used to treat anaemia in chronic kidney disease. In the pathophysiological state, kidney perivascular cells contribute to the progression of kidney fibrosis, partly via transdifferentiation into myofibroblasts. Moreover, perivascular cells are now recognized as major innate immune sentinels in the kidney that produce pro-inflammatory cytokines and chemokines following injury. These mediators promote immune cell infiltration, leading to persistent inflammation and progression of kidney fibrosis. The crosstalk between perivascular cells and tubular epithelial, immune and endothelial cells is therefore a key process in physiological and pathophysiological states. Here, we examine the multiple roles of kidney perivascular cells in health and disease, focusing on the latest advances in this field of research.

Key points

  • Perivascular niches in the kidney comprise heterogeneous cell populations, including pericytes and fibroblasts, with distinct functions. These perivascular cells have crucial roles in maintaining homeostasis in the kidney.

  • Pericytes maintain microvascular networks by stabilizing the vasculature and modulating the constriction of capillaries. In pathological states, such as ischaemia–reperfusion, pericytes contribute to the ‘no-reflow’ phenomenon.

  • A subset of kidney perivascular cells can produce and secrete erythropoietin; hypoxia-inducible factor-prolyl hydroxylase inhibitors can boost this secretion and are used for the treatment of anaemia in chronic kidney disease.

  • Perivascular cells or platelet-derived growth factor receptor-β+ (PDGFRβ+) pericytes synthesize and secrete various intracellular complement proteins and contribute to expression of collagen and extracellular matrix observed during the development of kidney fibrosis.

  • In pathophysiological states, kidney perivascular cells contribute to the progression of kidney fibrosis, partly by transdifferentiating into myofibroblasts.

  • Perivascular cells are major innate immune sentinels in the kidney and produce pro-inflammatory cytokines and chemokines after injury; these mediators promote immune cell infiltration, leading to persistent inflammation and progression of kidney fibrosis.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Pericytes, macrophages and sympathetic nerve terminals in the kidney microenvironment.
Fig. 2: Pericytes regulate microvascular blood flow.
Fig. 3: Oxygen-sensing system via the HIF-PH–HIF axis.
Fig. 4: Origin of myofibroblasts.
Fig. 5: Crosstalk between kidney perivascular cells or myofibroblasts, and adjacent cells in the pathophysiological state.
Fig. 6: Complement in the kidney tissue microenvironment contributes to tubulointerstitial fibrosis.

References

  1. Webster, A. C., Nagler, E. V., Morton, R. L. & Masson, P. Chronic kidney disease. Lancet 389, 1238–1252 (2017).

    Article  PubMed  Google Scholar 

  2. Eckardt, K. U. et al. Evolving importance of kidney disease: from subspecialty to global health burden. Lancet 382, 158–169 (2013).

    Article  PubMed  Google Scholar 

  3. Keith, D. S., Nichols, G. A., Gullion, C. M., Brown, J. B. & Smith, D. H. Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization. Arch. Intern. Med. 164, 659–663 (2004).

    Article  PubMed  Google Scholar 

  4. Go, A. S., Chertow, G. M., Fan, D., McCulloch, C. E. & Hsu, C. Y. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N. Engl. J. Med. 351, 1296–1305 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. National Kidney, F. KDOQI clinical practice guideline for diabetes and CKD: 2012 update. Am. J. Kidney Dis. 60, 850–886 (2012).

    Article  Google Scholar 

  6. United States Renal Data System. USRDS 2013 Annual Data Report: Atlas of Chronic Kidney Disease and End-stage Renal Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Digestive and Kidney Diseases, Vol. 2014 (Bethesda, 2013).

  7. Souma, T. et al. Plasticity of renal erythropoietin-producing cells governs fibrosis. J. Am. Soc. Nephrol. 24, 1599–1616 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Humphreys, B. D. et al. Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am. J. Pathol. 176, 85–97 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Asada, N. et al. Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice. J. Clin. Invest. 121, 3981–3990 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lin, S. L., Kisseleva, T., Brenner, D. A. & Duffield, J. S. Pericytes and perivascular fibroblasts are the primary source of collagen-producing cells in obstructive fibrosis of the kidney. Am. J. Pathol. 173, 1617–1627 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Leaf, I. A. et al. Pericyte MyD88 and IRAK4 control inflammatory and fibrotic responses to tissue injury. J. Clin. Invest. 127, 321–334 (2017).

    Article  PubMed  Google Scholar 

  12. Stark, K. et al. Capillary and arteriolar pericytes attract innate leukocytes exiting through venules and ‘instruct’ them with pattern-recognition and motility programs. Nat. Immunol. 14, 41–51 (2013).

    Article  CAS  PubMed  Google Scholar 

  13. Kaneko, K. et al. Lineage tracing analysis defines erythropoietin-producing cells as a distinct subpopulation of resident fibroblasts with unique behaviors. Kidney Int. 102, 280–292 (2022).

    Article  CAS  PubMed  Google Scholar 

  14. Broeker, K. A. E. et al. Different subpopulations of kidney interstitial cells produce erythropoietin and factors supporting tissue oxygenation in response to hypoxia in vivo. Kidney Int. 98, 918–931 (2020).

    Article  CAS  PubMed  Google Scholar 

  15. Chang, Y. T. et al. DNA methyltransferase inhibition restores erythropoietin production in fibrotic murine kidneys. J. Clin. Invest. 126, 721–731 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Shaw, I., Rider, S., Mullins, J., Hughes, J. & Peault, B. Pericytes in the renal vasculature: roles in health and disease. Nat. Rev. Nephrol. 14, 521–534 (2018).

    Article  CAS  PubMed  Google Scholar 

  17. Lin, A. et al. Mural cells: potential therapeutic targets to bridge cardiovascular disease and neurodegeneration. Cells 10, 593 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Boyle, S. C., Liu, Z. & Kopan, R. Notch signaling is required for the formation of mesangial cells from a stromal mesenchyme precursor during kidney development. Development 141, 346–354 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lemos, D. R. et al. Maintenance of vascular integrity by pericytes is essential for normal kidney function. Am. J. Physiol. Renal Physiol. 311, F1230–F1242 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Armulik, A., Genove, G. & Betsholtz, C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev. Cell 21, 193–215 (2011).

    Article  CAS  PubMed  Google Scholar 

  21. Sims, D. E. The pericyte — a review. Tissue Cell 18, 153–174 (1986).

    Article  CAS  PubMed  Google Scholar 

  22. Kennedy-Lydon, T. M., Crawford, C., Wildman, S. S. & Peppiatt-Wildman, C. M. Renal pericytes: regulators of medullary blood flow. Acta Physiol. 207, 212–225 (2013).

    Article  CAS  Google Scholar 

  23. Teichert, M. et al. Pericyte-expressed Tie2 controls angiogenesis and vessel maturation. Nat. Commun. 8, 16106 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Payne, L. B. et al. The pericyte microenvironment during vascular development. Microcirculation 26, e12554 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Kramann, R. et al. Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis. Cell Stem Cell 16, 51–66 (2015).

    Article  CAS  PubMed  Google Scholar 

  26. Murray, I. R. et al. αv integrins on mesenchymal cells regulate skeletal and cardiac muscle fibrosis. Nat. Commun. 8, 1118 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Volz, K. S. et al. Pericytes are progenitors for coronary artery smooth muscle. eLife 4, e10036 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Crisan, M. et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3, 301–313 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Meyers, C. A. et al. Early immunomodulatory effects of implanted human perivascular stromal cells during bone formation. Tissue Eng. Part. A 24, 448–457 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Tanaka, S. et al. Sphingosine 1-phosphate signaling in perivascular cells enhances inflammation and fibrosis in the kidney. Sci. Transl. Med. 14, eabj2681 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Li, Q., Yu, Y., Bischoff, J., Mulliken, J. B. & Olsen, B. R. Differential expression of CD146 in tissues and endothelial cells derived from infantile haemangioma and normal human skin. J. Pathol. 201, 296–302 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Ozerdem, U., Grako, K. A., Dahlin-Huppe, K., Monosov, E. & Stallcup, W. B. NG2 proteoglycan is expressed exclusively by mural cells during vascular morphogenesis. Dev. Dyn. 222, 218–227 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Nehls, V. & Drenckhahn, D. Heterogeneity of microvascular pericytes for smooth muscle type alpha-actin. J. Cell Biol. 113, 147–154 (1991).

    Article  CAS  PubMed  Google Scholar 

  34. Lemos, D. R. et al. Interleukin-1β activates a MYC-dependent metabolic switch in kidney stromal cells necessary for progressive tubulointerstitial fibrosis. J. Am. Soc. Nephrol. 29, 1690–1705 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Perry, H. M. et al. Perivascular CD73+ cells attenuate inflammation and interstitial fibrosis in the kidney microenvironment. Am. J. Physiol. Renal Physiol. 317, F658–F669 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kramann, R., Wongboonsin, J., Chang-Panesso, M., Machado, F. G. & Humphreys, B. D. Gli1+ pericyte loss induces capillary rarefaction and proximal tubular injury. J. Am. Soc. Nephrol. 28, 776–784 (2017).

    Article  CAS  PubMed  Google Scholar 

  37. Maeda, K. et al. Identification of meflin as a potential marker for mesenchymal stromal cells. Sci. Rep. 6, 22288 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Minatoguchi, S. et al. A novel renal perivascular mesenchymal cell subset gives rise to fibroblasts distinct from classic myofibroblasts. Sci. Rep. 12, 5389 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Stefanska, A. et al. Human kidney pericytes produce renin. Kidney Int. 90, 1251–1261 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Freitas, F. & Attwell, D. Pericyte-mediated constriction of renal capillaries evokes no-reflow and kidney injury following ischaemia. eLife 11, e74211 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Crislip, G. R., O’Connor, P. M., Wei, Q. & Sullivan, J. C. Vasa recta pericyte density is negatively associated with vascular congestion in the renal medulla following ischemia reperfusion in rats. Am. J. Physiol. Renal Physiol. 313, F1097–F1105 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Kwon, O., Hong, S. M., Sutton, T. A. & Temm, C. J. Preservation of peritubular capillary endothelial integrity and increasing pericytes may be critical to recovery from postischemic acute kidney injury. Am. J. Physiol. Renal Physiol. 295, F351–F359 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Peppiatt, C. M., Howarth, C., Mobbs, P. & Attwell, D. Bidirectional control of CNS capillary diameter by pericytes. Nature 443, 700–704 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Crawford, C., Wildman, S. S., Kelly, M. C., Kennedy-Lydon, T. M. & Peppiatt-Wildman, C. M. Sympathetic nerve-derived ATP regulates renal medullary vasa recta diameter via pericyte cells: a role for regulating medullary blood flow. Front. Physiol. 4, 307 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Crawford, C. et al. An intact kidney slice model to investigate vasa recta properties and function in situ. Nephron. Physiol. 120, p17–p31 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Bruzzone, R., Hormuzdi, S. G., Barbe, M. T., Herb, A. & Monyer, H. Pannexins, a family of gap junction proteins expressed in brain. Proc. Natl Acad. Sci. USA 100, 13644–13649 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Jankowski, J. et al. Epithelial and endothelial pannexin1 channels mediate AKI. J. Am. Soc. Nephrol. 29, 1887–1899 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hasegawa, S. et al. Comprehensive three-dimensional analysis (CUBIC-kidney) visualizes abnormal renal sympathetic nerves after ischemia/reperfusion injury. Kidney Int. 96, 129–138 (2019).

    Article  PubMed  Google Scholar 

  49. Alejandro, V. et al. Mechanisms of filtration failure during postischemic injury of the human kidney. A study of the reperfused renal allograft. J. Clin. Invest. 95, 820–831 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Brodsky, S. V. et al. Endothelial dysfunction in ischemic acute renal failure: rescue by transplanted endothelial cells. Am. J. Physiol. Renal Physiol. 282, F1140–F1149 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. Nangaku, M. Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J. Am. Soc. Nephrol. 17, 17–25 (2006).

    Article  CAS  PubMed  Google Scholar 

  52. Tanaka, S., Tanaka, T. & Nangaku, M. Hypoxia as a key player in the AKI-to-CKD transition. Am. J. Physiol. Renal Physiol. 307, F1187–F1195 (2014).

    Article  CAS  PubMed  Google Scholar 

  53. Souma, T. et al. Erythropoietin synthesis in renal myofibroblasts is restored by activation of hypoxia signaling. J. Am. Soc. Nephrol. 27, 428–438 (2016).

    Article  CAS  PubMed  Google Scholar 

  54. Minamishima, Y. A. et al. Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure. Blood 111, 3236–3244 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sato, K. et al. An immortalized cell line derived from renal erythropoietin-producing (REP) cells demonstrates their potential to transform into myofibroblasts. Sci. Rep. 9, 11254 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Besarab, A. et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N. Engl. J. Med. 339, 584–590 (1998).

    Article  CAS  PubMed  Google Scholar 

  57. Drueke, T. B. et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N. Engl. J. Med. 355, 2071–2084 (2006).

    Article  CAS  PubMed  Google Scholar 

  58. Pfeffer, M. A. et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N. Engl. J. Med. 361, 2019–2032 (2009).

    Article  PubMed  Google Scholar 

  59. Singh, A. K. et al. Correction of anemia with epoetin alfa in chronic kidney disease. N. Engl. J. Med. 355, 2085–2098 (2006).

    Article  CAS  PubMed  Google Scholar 

  60. Szczech, L. A. et al. Secondary analysis of the CHOIR trial epoetin-α dose and achieved hemoglobin outcomes. Kidney Int. 74, 791–798 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Bernhardt, W. M. et al. Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD. J. Am. Soc. Nephrol. 21, 2151–2156 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Kobayashi, H., Davidoff, O., Pujari-Palmer, S., Drevin, M. & Haase, V. H. EPO synthesis induced by HIF-PHD inhibition is dependent on myofibroblast transdifferentiation and colocalizes with non-injured nephron segments in murine kidney fibrosis. Acta Physiol. 235, e13826 (2022).

    Article  CAS  Google Scholar 

  63. Holdstock, L. et al. Four-week studies of oral hypoxia-inducible factor-prolyl hydroxylase inhibitor GSK1278863 for treatment of anemia. J. Am. Soc. Nephrol. 27, 1234–1244 (2016).

    Article  CAS  PubMed  Google Scholar 

  64. Sugahara, M. et al. Prolyl hydroxylase domain inhibitor protects against metabolic disorders and associated kidney disease in obese type 2 diabetic mice. J. Am. Soc. Nephrol. 31, 560–577 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Pan, S. Y. et al. Kidney pericyte hypoxia-inducible factor regulates erythropoiesis but not kidney fibrosis. Kidney Int. 99, 1354–1368 (2021).

    Article  CAS  PubMed  Google Scholar 

  66. Locatelli, F. & Del Vecchio, L. Hypoxia-inducible factor-prolyl hydroxyl domain inhibitors: from theoretical superiority to clinical noninferiority compared with current ESAs? J. Am. Soc. Nephrol. 33, 1966–1979 (2022).

    Article  CAS  PubMed  Google Scholar 

  67. Sugahara, M., Tanaka, T. & Nangaku, M. Future perspectives of anemia management in chronic kidney disease using hypoxia-inducible factor-prolyl hydroxylase inhibitors. Pharmacol. Ther. 239, 108272 (2022).

    Article  CAS  PubMed  Google Scholar 

  68. Quaggin, S. E. & Kapus, A. Scar wars: mapping the fate of epithelial-mesenchymal-myofibroblast transition. Kidney Int. 80, 41–50 (2011).

    Article  PubMed  Google Scholar 

  69. Deng, Y. et al. Blocking protein phosphatase 2A signaling prevents endothelial-to-mesenchymal transition and renal fibrosis: a peptide-based drug therapy. Sci. Rep. 6, 19821 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Zeisberg, E. M., Potenta, S. E., Sugimoto, H., Zeisberg, M. & Kalluri, R. Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition. J. Am. Soc. Nephrol. 19, 2282–2287 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Phua, Y. L., Martel, N., Pennisi, D. J., Little, M. H. & Wilkinson, L. Distinct sites of renal fibrosis in Crim1 mutant mice arise from multiple cellular origins. J. Pathol. 229, 685–696 (2013).

    Article  CAS  PubMed  Google Scholar 

  72. Tang, Y., Harrington, A., Yang, X., Friesel, R. E. & Liaw, L. The contribution of the Tie2+ lineage to primitive and definitive hematopoietic cells. Genesis 48, 563–567 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. De Palma, M. et al. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8, 211–226 (2005).

    Article  PubMed  Google Scholar 

  74. Cai, J., Kehoe, O., Smith, G. M., Hykin, P. & Boulton, M. E. The angiopoietin/Tie-2 system regulates pericyte survival and recruitment in diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 49, 2163–2171 (2008).

    Article  PubMed  Google Scholar 

  75. LeBleu, V. S. et al. Origin and function of myofibroblasts in kidney fibrosis. Nat. Med. 19, 1047–1053 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Chen, M. J., Yokomizo, T., Zeigler, B. M., Dzierzak, E. & Speck, N. A. Runx1 is required for the endothelial to haematopoietic cell transition but not thereafter. Nature 457, 887–891 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Reich, B. et al. Fibrocytes develop outside the kidney but contribute to renal fibrosis in a mouse model. Kidney Int. 84, 78–89 (2013).

    Article  CAS  PubMed  Google Scholar 

  78. Kramann, R. et al. Parabiosis and single-cell RNA sequencing reveal a limited contribution of monocytes to myofibroblasts in kidney fibrosis. JCI Insight 3, e99561 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Kuppe, C. et al. Decoding myofibroblast origins in human kidney fibrosis. Nature 589, 281–286 (2021).

    Article  CAS  PubMed  Google Scholar 

  80. Shaw, I. W. et al. Aging modulates the effects of ischemic injury upon mesenchymal cells within the renal interstitium and microvasculature. Stem Cell Transl. Med. 10, 1232–1248 (2021).

    Article  CAS  Google Scholar 

  81. Zhou, D. et al. Tubule-derived wnts are required for fibroblast activation and kidney fibrosis. J. Am. Soc. Nephrol. 28, 2322–2336 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Maarouf, O. H. et al. Paracrine wnt1 drives interstitial fibrosis without inflammation by tubulointerstitial cross-talk. J. Am. Soc. Nephrol. 27, 781–790 (2016).

    Article  CAS  PubMed  Google Scholar 

  83. Ding, H. et al. Sonic hedgehog signaling mediates epithelial-mesenchymal communication and promotes renal fibrosis. J. Am. Soc. Nephrol. 23, 801–813 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Fabian, S. L. et al. Hedgehog-Gli pathway activation during kidney fibrosis. Am. J. Pathol. 180, 1441–1453 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Kramann, R. et al. Pharmacological GLI2 inhibition prevents myofibroblast cell-cycle progression and reduces kidney fibrosis. J. Clin. Invest. 125, 2935–2951 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Liu, X. et al. Tubule-derived exosomes play a central role in fibroblast activation and kidney fibrosis. Kidney Int. 97, 1181–1195 (2020).

    Article  CAS  PubMed  Google Scholar 

  87. Bielesz, B. et al. Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans. J. Clin. Invest. 120, 4040–4054 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Li, H. et al. Upregulation of HER2 in tubular epithelial cell drives fibroblast activation and renal fibrosis. Kidney Int. 96, 674–688 (2019).

    Article  PubMed  Google Scholar 

  89. Dwivedi, N. et al. Epithelial vasopressin type-2 receptors regulate myofibroblasts by a yap-ccn2-dependent mechanism in polycystic kidney disease. J. Am. Soc. Nephrol. 31, 1697–1710 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Xu, X. et al. High-fidelity CRISPR/Cas9-based gene-specific hydroxymethylation rescues gene expression and attenuates renal fibrosis. Nat. Commun. 9, 3509 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Chou, Y. H. et al. Methylation in pericytes after acute injury promotes chronic kidney disease. J. Clin. Invest. 130, 4845–4857 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Tanaka, S. et al. Vascular adhesion protein-1 enhances neutrophil infiltration by generation of hydrogen peroxide in renal ischemia/reperfusion injury. Kidney Int. 92, 154–164 (2017).

    Article  CAS  PubMed  Google Scholar 

  93. Fritzemeier, R. et al. Discovery of in vivo active sphingosine-1-phosphate transporter (spns2) inhibitors. J. Med. Chem. 65, 7656–7681 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Hafizi, R. et al. Sphk1 and Sphk2 differentially regulate erythropoietin synthesis in mouse renal interstitial fibroblast-like cells. Int. J. Mol. Sci. 23, 5882 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Hafizi, R., Imeri, F., Wenger, R. H. & Huwiler, A. S1P stimulates erythropoietin production in mouse renal interstitial fibroblasts by S1P1 and S1P3 receptor activation and HIF-2α stabilization. Int. J. Mol. Sci. 22, 9467 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Pai, C. H. et al. Targeting fibroblast CD248 attenuates CCL17-expressing macrophages and tissue fibrosis. Sci. Rep. 10, 16772 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Wu, Y. et al. miR-145a regulates pericyte dysfunction in a murine model of sepsis. J. Infect. Dis. 222, 1037–1045 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Seki, E. et al. TLR4 enhances TGF-β signaling and hepatic fibrosis. Nat. Med. 13, 1324–1332 (2007).

    Article  CAS  PubMed  Google Scholar 

  99. Paik, Y. H. et al. Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells. Hepatology 37, 1043–1055 (2003).

    Article  CAS  PubMed  Google Scholar 

  100. Guo, J. et al. Functional linkage of cirrhosis-predictive single nucleotide polymorphisms of Toll-like receptor 4 to hepatic stellate cell responses. Hepatology 49, 960–968 (2009).

    Article  CAS  PubMed  Google Scholar 

  101. Chen, Y. T. et al. Platelet-derived growth factor receptor signaling activates pericyte-myofibroblast transition in obstructive and post-ischemic kidney fibrosis. Kidney Int. 80, 1170–1181 (2011).

    Article  CAS  PubMed  Google Scholar 

  102. Conway, B. R. et al. Kidney single-cell atlas reveals myeloid heterogeneity in progression and regression of kidney disease. J. Am. Soc. Nephrol. 31, 2833–2854 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Kida, Y., Ieronimakis, N., Schrimpf, C., Reyes, M. & Duffield, J. S. EphrinB2 reverse signaling protects against capillary rarefaction and fibrosis after kidney injury. J. Am. Soc. Nephrol. 24, 559–572 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Thurman, J. M. Complement in kidney disease: core curriculum 2015. Am. J. Kidney Dis. 65, 156–168 (2015).

    Article  PubMed  Google Scholar 

  105. Reis, E. S., Mastellos, D. C., Hajishengallis, G. & Lambris, J. D. New insights into the immune functions of complement. Nat. Rev. Immunol. 19, 503–516 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Kemper, C. et al. Complement: the road less traveled. J. Immunol. 210, 119–125 (2023).

    Article  CAS  PubMed  Google Scholar 

  107. Anders, H. J., Fernandez-Juarez, G. M., Vaglio, A., Romagnani, P. & Floege, J. CKD therapy to improve outcomes of immune-mediated glomerular diseases. Nephrol. Dial. Transpl. gfad069 (2023).

  108. Merle, N. S., Church, S. E., Fremeaux-Bacchi, V. & Roumenina, L. T. Complement system part I — molecular mechanisms of activation and regulation. Front. Immunol. 6, 262 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Xavier, S. et al. Pericytes and immune cells contribute to complement activation in tubulointerstitial fibrosis. Am. J. Physiol. Renal Physiol. 312, F516–F532 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Xavier, S. et al. Complement C1r serine protease contributes to kidney fibrosis. Am. J. Physiol. Renal Physiol. 317, F1293–F1304 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Portilla, D. & Xavier, S. Role of intracellular complement activation in kidney fibrosis. Br. J. Pharmacol. 178, 2880–2891 (2021).

    Article  CAS  PubMed  Google Scholar 

  112. Sahu, R. K. et al. Folic acid-mediated fibrosis is driven by C5a receptor 1-mediated activation of kidney myeloid cells. Am. J. Physiol. Renal Physiol. 322, F597–F610 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Lech, M. et al. Macrophage phenotype controls long-term AKI outcomes–kidney regeneration versus atrophy. J. Am. Soc. Nephrol. 25, 292–304 (2014).

    Article  CAS  PubMed  Google Scholar 

  114. Venkatachalam, M. A., Weinberg, J. M., Kriz, W. & Bidani, A. K. Failed tubule recovery, AKI-CKD transition, and kidney disease progression. J. Am. Soc. Nephrol. 26, 1765–1776 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Castellano, G. et al. Complement activation during ischemia/reperfusion injury induces pericyte-to-myofibroblast transdifferentiation regulating peritubular capillary lumen reduction through pERK signaling. Front. Immunol. 9, 1002 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Naba, A. et al. The matrisome: in silico definition and in vivo characterization by proteomics of normal and tumor extracellular matrices. Mol. Cell Proteom. 11, M111 014647 (2012).

    Article  Google Scholar 

  117. Wooden, B., Estebanez, B. T., Navarro-Torres, M. & Bomback, A. S. Complement inhibitors for kidney disease. Nephrol. Dial. Transpl. gfad079 https://doi.org/10.1093/ndt/gfad079 (2023).

  118. Gerhardt, L. M. S. et al. Lineage tracing and single-nucleus multiomics reveal novel features of adaptive and maladaptive repair after acute kidney injury. J Am Soc Nephrol, 34, 554–571 (2023).

    Article  PubMed  Google Scholar 

  119. Schiessl, I. M. et al. Renal interstitial platelet-derived growth factor receptor-β cells support proximal tubular regeneration. J. Am. Soc. Nephrol. 29, 1383–1396 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Nakamura, J. et al. Myofibroblasts acquire retinoic acid-producing ability during fibroblast-to-myofibroblast transition following kidney injury. Kidney Int. 95, 526–539 (2019).

    Article  CAS  PubMed  Google Scholar 

  121. Nakagawa, T. et al. Role of PDGF B-chain and PDGF receptors in rat tubular regeneration after acute injury. Am. J. Pathol. 155, 1689–1699 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Hara, A. et al. Roles of the mesenchymal stromal/stem cell marker meflin in cardiac tissue repair and the development of diastolic dysfunction. Circ. Res. 125, 414–430 (2019).

    Article  CAS  PubMed  Google Scholar 

  123. Shi, M. et al. Effects of erythropoietin receptor activity on angiogenesis, tubular injury, and fibrosis in acute kidney injury: a “U-shaped” relationship. Am. J. Physiol. Renal Physiol. 314, F501–F516 (2018).

    Article  CAS  PubMed  Google Scholar 

  124. Zhou, D. et al. Fibroblast-specific β-catenin signaling dictates the outcome of AKI. J. Am. Soc. Nephrol. 29, 1257–1271 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Fujigaki, Y. et al. Transient myofibroblast differentiation of interstitial fibroblastic cells relevant to tubular dilatation in uranyl acetate-induced acute renal failure in rats. Virchows Arch. 446, 164–176 (2005).

    Article  CAS  PubMed  Google Scholar 

  126. Sun, D. F., Fujigaki, Y., Fujimoto, T., Yonemura, K. & Hishida, A. Possible involvement of myofibroblasts in cellular recovery of uranyl acetate-induced acute renal failure in rats. Am. J. Pathol. 157, 1321–1335 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Stallcup, W. B. The NG2 proteoglycan in pericyte biology. Adv. Exp. Med. Biol. 1109, 5–19 (2018).

    Article  CAS  PubMed  Google Scholar 

  128. Jensen, A. R. et al. Neer award 2018: platelet-derived growth factor receptor α co-expression typifies a subset of platelet-derived growth factor receptor β-positive progenitor cells that contribute to fatty degeneration and fibrosis of the murine rotator cuff. J. Shoulder Elbow Surg. 27, 1149–1161 (2018).

    Article  PubMed  Google Scholar 

  129. He, L. et al. Single-cell RNA sequencing of mouse brain and lung vascular and vessel-associated cell types. Sci. Data 5, 180160 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Enstrom, A., Carlsson, R., Ozen, I. & Paul, G. RGS5: a novel role as a hypoxia-responsive protein that suppresses chemokinetic and chemotactic migration in brain pericytes. Biol. Open 11, bio059371 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Roth, M. et al. Regulator of G-protein signaling 5 regulates the shift from perivascular to parenchymal pericytes in the chronic phase after stroke. FASEB J. 33, 8990–8998 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Maxwell, P. H. et al. Identification of the renal erythropoietin-producing cells using transgenic mice. Kidney Int. 44, 1149–1162 (1993).

    Article  CAS  PubMed  Google Scholar 

  133. Rockey, D. C., Weymouth, N. & Shi, Z. Smooth muscle α actin (Acta2) and myofibroblast function during hepatic wound healing. PLoS One 8, e77166 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank D. Rosin for careful reading of the manuscript before submission. Work in the laboratory of S.T. is funded by JSPS KAKENHI (JP21K20894, JP22K16232), AMED (JP22gm6510016), the Ichiro Kanehara Foundation, MSD Life Science Foundation, the Uehara Memorial Foundation, Life Science Foundation of Japan, the Salt Science Research Foundation (2327), Research Fund of Mitsukoshi Health and Welfare Foundation 2022, and Kobayashi Foundation. Work in the laboratory of D.P. is funded by National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01 DK 12262401A1). Work in the laboratory of M.D.O. is supported by the NIDDK (R01DK085259 and R01DK123248).

Author information

Authors and Affiliations

  1. Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan

    Shinji Tanaka

  2. Division of Nephrology and Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia, Charlottesville, VA, USA

    Didier Portilla & Mark D. Okusa

Authors
  1. Shinji Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Didier Portilla
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mark D. Okusa
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors made substantial contributions to discussions of the content and wrote, reviewed or edited the manuscript before submission.

Corresponding authors

Correspondence to Shinji Tanaka or Mark D. Okusa.

Ethics declarations

Competing Interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Nephrology thanks R. Kramann, S.-L. Lin, Y. Liu and S. Zhuang for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tanaka, S., Portilla, D. & Okusa, M.D. Role of perivascular cells in kidney homeostasis, inflammation, repair and fibrosis. Nat Rev Nephrol 19, 721–732 (2023). https://doi.org/10.1038/s41581-023-00752-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41581-023-00752-7

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing