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.

  • Review Article
  • Published:

Role of triglyceride-rich lipoproteins in diabetic nephropathy

Abstract

Diabetic nephropathy is an increasingly important cause of morbidity and mortality worldwide. A large body of evidence suggests that dyslipidemia has an important role in the progression of kidney disease in patients with diabetes. Lipids may induce renal injury by stimulating TGF-β, thereby inducing the production of reactive oxygen species and causing damage to the glomeruli and glomerular glycocalyx. Findings from basic and clinical studies strongly suggest that excess amounts of a variety of lipoproteins and lipids worsens diabetes-associated microvascular and macrovascular disease, increases glomerular injury, increases tubulointerstitial fibrosis, and accelerates the progression of diabetic nephropathy. The increasing prevalence of obesity, type 2 diabetes mellitus, and diabetic nephropathy means that interventions that can interrupt the pathophysiological cascade of events induced by lipoproteins and lipids could enable major life and cost savings. This Review discusses the structural, cellular, and microscopic findings associated with diabetic nephropathy and the influence of lipoproteins, specifically triglyceride-rich lipoproteins (TGRLs), on the development and perpetuation of diabetic nephropathy. Some of the accepted and hypothesized mechanisms of renal injury relating to TGRLs are also described.

Key Points

  • In patients with diabetes, an excess of a variety of lipoproteins and lipids worsens microvascular and macrovascular disease, increases glomerular injury, increases tubulointerstitial fibrosis, and accelerates progression of diabetic nephropathy

  • Lipid abnormalities associated with diabetic nephropathy include high plasma levels of VLDL, IDL, and LDL, and low concentrations of HDL

  • Lipids may induce renal injury by stimulating TGF-β, thereby inducing the production of reactive oxygen species and causing damage to the glomeruli and glomerular glycocalyx

  • Triglyceride-rich lipoproteins can activate monocytes, degrade glycocalyx, and increase permeability of the glomerular filtration barrier, which may contribute to the progression of diabetic nephropathy

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

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

Figure 1: Key mediators of glomerular remodeling in diabetic nephropathy.
Figure 2: Effects of type 1 diabetes on endothelial layer structure.
Figure 3: Electron microscopy image of the endothelial glycocalyx in a coronary capillary.92
Figure 4: VLDL lipolysis products induce lipid droplets in THP-1 monocytes.98
Figure 5: The effects of TGRLs in the kidney in diabetes.

Similar content being viewed by others

References

  1. Brown, W. V. Microvascular complications of diabetes mellitus: renal protection accompanies cardiovascular protection. Am. J. Cardiol. 102, 10L–13L (2008).

    Article  PubMed  Google Scholar 

  2. Endlich, K., Kriz, W. & Witzgall, R. Update in podocyte biology. Curr. Opin. Nephrol. Hypertens. 10, 331–340 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Komers, R., Meyer, T. W. & Anderson, S. in Diseases of the Kidney and Urinary Tract Vol. 3 Ch. 91 (ed. Schrier, R. W.) 2380–2404 (Lippincott Williams & Wilkins, 2007).

    Google Scholar 

  4. Ziyadeh, F. N. & Wolf, G. Pathogenesis of the podocytopathy and proteinuria in diabetic glomerulopathy. Curr. Diabetes Rev. 4, 39–45 (2008).

    Article  CAS  PubMed  Google Scholar 

  5. Hauser, P. V., Collino, F., Bussolati, B. & Camussi, G. Nephrin and endothelial injury. Curr. Opin. Nephrol. Hypertens. 18, 3–8 (2009).

    Article  CAS  PubMed  Google Scholar 

  6. Ishigaki, N. et al. Involvement of glomerular SREBP-1c in diabetic nephropathy. Biochem. Biophys. Res. Commun. 364, 502–508 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Tham, D. M. et al. Angiotensin II injures the arterial wall causing increased aortic stiffening in apolipoprotein E-deficient mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 283, R1442–R1449 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Park, S. et al. Major role for ACE-independent intrarenal ANGII formation in type II diabetes. Am. J. Physiol. Renal Physiol. 298, F37–F48 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Hakroush, S. et al. Effects of increased renal tubular vascular endothelial growth factor (VEGF) on fibrosis, cyst formation, and glomerular disease. Am. J. Pathol. 175, 1883–1895 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Luo, P. et al. Glomerular 20-HETE, EETs, and TGF-beta1 in diabetic nephropathy. Am. J. Physiol. Renal Physiol. 296, F556–F563 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Nordquist, L., Brown, R., Fasching, A., Persson, P. & Palm, F. Proinsulin C-peptide reduces diabetes-induced glomerular hyperfiltration via efferent arteriole dilation and inhibition of tubular sodium reabsorption. Am. J. Physiol. Renal Physiol. 297, F1265–F1272 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Segerer, S., Kretzler, M., Strutz, G. & Schlondorff, D. in Diseases of the Kidney and Urinary Tract Vol. 2 Ch 57 (ed. Schrier, R. W.) 1438–1463 (Lippincott Williams & Wilkins, 2007).

    Google Scholar 

  13. Tesch, G. H. MCP-1/CCL2: a new diagnostic marker and therapeutic target for progressive renal injury in diabetic nephropathy. Am. J. Physiol. Renal Physiol. 294, F697–F701 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Ruan, X. Z., Varghese, Z., Powis, S. H. & Moorhead, J. F. Human mesangial cells express inducible macrophage scavenger receptor. Kidney Int. 56, 440–451 (1999).

    Article  CAS  PubMed  Google Scholar 

  15. Hovind, P. et al. Predictors for the development of microalbuminuria and macroalbuminuria in patients with type 1 diabetes: inception cohort study. BMJ 328, 1105 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Klahr, S., Schreiner, G. & Ichikawa, I. The progression of renal disease. N. Engl. J. Med. 318, 1657–1666 (1988).

    Article  CAS  PubMed  Google Scholar 

  17. Coonrod, B. A. et al. Predictors of microalbuminuria in individuals with IDDM. Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes Care 16, 1376–1383 (1993).

    Article  CAS  PubMed  Google Scholar 

  18. Hunsicker, L. G. et al. Predictors of the progression of renal disease in the Modification of Diet in Renal Disease Study. Kidney Int. 51, 1908–1919 (1997).

    Article  CAS  PubMed  Google Scholar 

  19. Predictors of the development of microalbuminuria in patients with type 1 diabetes mellitus: a seven-year prospective study. The Microalbuminuria Collaborative Study Group. Diabet. Med. 16, 918–925 (1999).

  20. Rossing, P., Hougaard, P. & Parving, H. H. Risk factors for development of incipient and overt diabetic nephropathy in type 1 diabetic patients: a 10-year prospective observational study. Diabetes Care 25, 859–864 (2002).

    Article  PubMed  Google Scholar 

  21. Orchard, T. J. et al. Prevalence of complications in IDDM by sex and duration. Pittsburgh Epidemiology of Diabetes Complications Study II. Diabetes 39, 1116–1124 (1990).

    Article  CAS  PubMed  Google Scholar 

  22. Caramori, M. L., Fioretto, P. & Mauer, M. The need for early predictors of diabetic nephropathy risk: is albumin excretion rate sufficient? Diabetes 49, 1399–1408 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Deckert, T., Feldt-Rasmussen, B., Borch-Johnsen, K., Jensen, T. & Kofoed-Enevoldsen, A. Albuminuria reflects widespread vascular damage. The Steno hypothesis. Diabetologia 32, 219–226 (1989).

    Article  CAS  PubMed  Google Scholar 

  24. Shoji, T. et al. Atherogenic lipoprotein changes in diabetic nephropathy. Atherosclerosis 156, 425–433 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Kashiwazaki, K. et al. Decreased release of lipoprotein lipase is associated with vascular endothelial damage in NIDDM patients with microalbuminuria. Diabetes Care 21, 2016–2020 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Dominguez, J. H. et al. Studies of renal injury III: lipid-induced nephropathy in type II diabetes. Kidney Int. 57, 92–104 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Fontbonne, A. et al. Hypertriglyceridaemia as a risk factor of coronary heart disease mortality in subjects with impaired glucose tolerance or diabetes. Results from the 11-year follow-up of the Paris Prospective Study. Diabetologia 32, 300–304 (1989).

    Article  CAS  PubMed  Google Scholar 

  28. Attman, P. O., Nyberg, G., William-Olsson, T., Knight-Gibson, C. & Alaupovic, P. Dyslipoproteinemia in diabetic renal failure. Kidney Int. 42, 1381–1389 (1992).

    Article  CAS  PubMed  Google Scholar 

  29. Yoshino, G., Hirano, T. & Kazumi, T. Atherogenic lipoproteins and diabetes mellitus. J. Diabetes Complications 16, 29–34 (2002).

    Article  PubMed  Google Scholar 

  30. Hirano, T. et al. Very low-density lipoprotein-apoprotein CI is increased in diabetic nephropathy: comparison with apoprotein CIII. Kidney Int. 63, 2171–2177 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Jenkins, A. J. et al. Lipoproteins in the DCCT/EDIC cohort: associations with diabetic nephropathy. Kidney Int. 64, 817–828 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Cockerill, G. W., Rye, K. A., Gamble, J. R., Vadas, M. A. & Barter, P. J. High-density lipoproteins inhibit cytokine-induced expression of endothelial cell adhesion molecules. Arterioscler. Thromb. Vasc. Biol. 15, 1987–1994 (1995).

    Article  CAS  PubMed  Google Scholar 

  33. Nelson, C. L. et al. Systemic and vascular inflammation is elevated in early IgA and type 1 diabetic nephropathies and relates to vascular disease risk factors and renal function. Nephrol. Dial. Transplant. 20, 2420–2426 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. Brown, M. L. et al. A macrophage receptor for apolipoprotein B48: cloning, expression, and atherosclerosis. Proc. Natl Acad. Sci. USA 97, 7488–7493 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Redgrave, T. G. Chylomicron metabolism. Biochem. Soc. Trans. 32, 79–82 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Hayashi, T. et al. Remarkable increase of apolipoprotein B48 level in diabetic patients with end-stage renal disease. Atherosclerosis 197, 154–158 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Hirano, T. Lipoprotein abnormalities in diabetic nephropathy. Kidney Int. Suppl. 71, S22–S24 (1999).

    Article  CAS  PubMed  Google Scholar 

  38. Blum, C. B. Dynamics of apolipoprotein E metabolism in humans. J. Lipid. Res. 23, 1308–1316 (1982).

    CAS  PubMed  Google Scholar 

  39. Nestel, P. J., Huff, M. W., Billington, T. & Fidge, N. H. Changes in the plasma lipoprotein distribution of apolipoproteins C-II, C-III1, C-III2 and apolipoprotein B after heparin-induced lipolysis. Biochim. Biophys. Acta 712, 94–102 (1982).

    Article  CAS  PubMed  Google Scholar 

  40. Kashyap, V. S. et al. Apolipoprotein E deficiency in mice: gene replacement and prevention of atherosclerosis using adenovirus vectors. J. Clin. Invest. 96, 1612–1620 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sacks, F. M. et al. VLDL, apolipoproteins, B, CIII, and E, and risk of recurrent coronary events in the Cholesterol and Recurrent Events (CARE) trial. Circulation 102, 1886–1892 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Campos, H., Perlov, D., Khoo, C. & Sacks, F. M. Distinct patterns of lipoproteins with apoB defined by presence of apoE or apoC-III in hypercholesterolemia and hypertriglyceridemia. J. Lipid Res. 42, 1239–1249 (2001).

    CAS  PubMed  Google Scholar 

  43. Bard, J. M. et al. Accumulation of triglyceride-rich lipoprotein in subjects with abdominal obesity: the biguanides and the prevention of the risk of obesity (BIGPRO) 1 study. Arterioscler. Thromb. Vasc. Biol. 21, 407–414 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Cohn, J. S., Patterson, B. W., Uffelman, K. D., Davignon, J. & Steiner, G. Rate of production of plasma and very-low-density lipoprotein (VLDL) apolipoprotein C-III is strongly related to the concentration and level of production of VLDL triglyceride in male subjects with different body weights and levels of insulin sensitivity. J. Clin. Endocrinol. Metab. 89, 3949–3955 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Veiraiah, A. Hyperglycemia, lipoprotein glycation, and vascular disease. Angiology 56, 431–438 (2005).

    Article  PubMed  Google Scholar 

  46. Bucala, R. et al. Modification of low density lipoprotein by advanced glycation end products contributes to the dyslipidemia of diabetes and renal insufficiency. Proc. Natl Acad. Sci. USA 91, 9441–9445 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Goh, S. Y. & Cooper, M. E. Clinical review: the role of advanced glycation end products in progression and complications of diabetes. J. Clin. Endocrinol. Metab. 93, 1143–1152 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Eto, M. et al. Apolipoprotein E genetic polymorphism, remnant lipoproteins, and nephropathy in type 2 diabetic patients. Am. J. Kidney Dis. 40, 243–251 (2002).

    Article  CAS  PubMed  Google Scholar 

  49. Hadjadj, S. et al. Lack of relationship in long-term type 1 diabetic patients between diabetic nephropathy and polymorphisms in apolipoprotein epsilon, lipoprotein lipase and cholesteryl ester transfer protein. Genetique de la Nephropathie Diabetique Study Group. Donnees Epidemiologiques sur le Syndrome d'Insulino-Resistance Study Group. Nephrol. Dial. Transplant. 15, 1971–1976 (2000).

    Article  CAS  PubMed  Google Scholar 

  50. Sun, L., Halaihel, N., Zhang, W., Rogers, T. & Levi, M. Role of sterol regulatory element-binding protein 1 in regulation of renal lipid metabolism and glomerulosclerosis in diabetes mellitus. J. Biol. Chem. 277, 18919–18927 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. Jenkins, A. J., Steele, J. S., Janus, E. D. & Best, J. D. Increased plasma apolipoprotein(a) levels in IDDM patients with microalbuminuria. Diabetes 40, 787–790 (1991).

    Article  CAS  PubMed  Google Scholar 

  52. Jerums, G. et al. Relationship of progressively increasing albuminuria to apoprotein(a) and blood pressure in type 2 (non-insulin-dependent) and type 1 (insulin-dependent) diabetic patients. Diabetologia 36, 1037–1044 (1993).

    Article  CAS  PubMed  Google Scholar 

  53. Anuurad, E. et al. High levels of inflammatory biomarkers are associated with increased allele-specific apolipoprotein(a) levels in African-Americans. J. Clin. Endocrinol. Metab. 93, 1482–1488 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ujihara, N. et al. Association between plasma oxidized low-density lipoprotein and diabetic nephropathy. Diabetes Res. Clin. Pract. 58, 109–114 (2002).

    Article  CAS  PubMed  Google Scholar 

  55. Jandeleit-Dahm, K. et al. Role of hyperlipidemia in progressive renal disease: focus on diabetic nephropathy. Kidney Int. Suppl. 71, S31–S36 (1999).

    Article  CAS  PubMed  Google Scholar 

  56. Massy, Z. A., Ma, J. Z., Louis, T. A. & Kasiske, B. L. Lipid-lowering therapy in patients with renal disease. Kidney Int. 48, 188–198 (1995).

    Article  CAS  PubMed  Google Scholar 

  57. Keane, W. F. Lipids and progressive renal disease: the cardio-renal link. Am. J. Kidney Dis. 34, xliii–xlvi (1999).

    Article  CAS  PubMed  Google Scholar 

  58. Buemi, M. et al. Statins and progressive renal disease. Med. Res. Rev. 22, 76–84 (2002).

    Article  CAS  PubMed  Google Scholar 

  59. Kappelle, P. J. et al. Atorvastatin affects low density lipoprotein and non-high density lipoprotein cholesterol relations with apolipoprotein B in type 2 diabetes mellitus: modification by triglycerides and cholesteryl ester transfer protein. Expert Opin. Ther. Targets 13, 743–751 (2009).

    Article  CAS  PubMed  Google Scholar 

  60. Fried, L. F., Orchard, T. J. & Kasiske, B. L. Effect of lipid reduction on the progression of renal disease: a meta-analysis. Kidney Int. 59, 260–269 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Athyros, V. G. et al. Effect of statin treatment on renal function and serum uric acid levels and their relation to vascular events in patients with coronary heart disease and metabolic syndrome: a subgroup analysis of the GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) Study. Nephrol. Dial. Transplant. 22, 118–127 (2007).

    Article  CAS  PubMed  Google Scholar 

  62. Collins, R., Armitage, J., Parish, S., Sleigh, P. & Peto, R. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 361, 2005–2016 (2003).

    Article  PubMed  Google Scholar 

  63. Keech, A. et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 366, 1849–1861 (2005).

    Article  CAS  PubMed  Google Scholar 

  64. Shin, S. J. et al. Peroxisome proliferator-activated receptor-alpha activator fenofibrate prevents high-fat diet-induced renal lipotoxicity in spontaneously hypertensive rats. Hypertens. Res. 32, 835–845 (2009).

    Article  CAS  PubMed  Google Scholar 

  65. Molitch, M. E. Management of dyslipidemias in patients with diabetes and chronic kidney disease. Clin. J. Am. Soc. Nephrol. 1, 1090–1099 (2006).

    Article  CAS  PubMed  Google Scholar 

  66. Cases, A. & Coll, E. Dyslipidemia and the progression of renal disease in chronic renal failure patients. Kidney Int. S87–S93 (2005).

  67. Casey, R. G., Joyce, M., Roche-Nagle, G., Chen, G. & Bouchier-Hayes, D. Pravastatin modulates early diabetic nephropathy in an experimental model of diabetic renal disease. J. Surg. Res. 123, 176–181 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. Dominguez, J., Wu, P., Packer, C. S., Temm, C. & Kelly, K. J. Lipotoxic and inflammatory phenotypes in rats with uncontrolled metabolic syndrome and nephropathy. Am. J. Physiol. Renal Physiol. 293, F670–F679 (2007).

    Article  CAS  PubMed  Google Scholar 

  69. Spencer, M. W. et al. Hyperglycemia and hyperlipidemia act synergistically to induce renal disease in LDL receptor-deficient BALB mice. Am. J. Nephrol. 24, 20–31 (2004).

    Article  CAS  PubMed  Google Scholar 

  70. Eiselein, L., Wilson, D., Lame, M. & Rutledge, J. C. Lipolysis products from triglyceride-rich lipoproteins increase endothelial permeability, perturb zonula occludens-1, F-actin, and induce apoptosis. Am. J. Physiol. Heart Circ. Physiol. 292, H2745–H2753 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Robinson, D. R., Prickett, J. D., Makoul, G. T., Steinberg, A. D. & Colvin, R. B. Dietary fish oil reduces progression of established renal disease in (NZB x NZW)F1 mice and delays renal disease in BXSB and MRL/1 strains. Arthritis Rheum. 29, 539–546 (1986).

    Article  CAS  PubMed  Google Scholar 

  72. An, W. S., Kim, H. J., Cho, K. H. & Vaziri, N. D. Omega-3 fatty acid supplementation attenuates oxidative stress, inflammation, and tubulointerstitial fibrosis in the remnant kidney. Am. J. Physiol. Renal Physiol. 297, F895–F903 (2009).

    Article  CAS  PubMed  Google Scholar 

  73. Kim, H. J., Moradi, H., Yuan, J., Norris, K. & Vaziri, N. D. Renal mass reduction results in accumulation of lipids and dysregulation of lipid regulatory proteins in the remnant kidney. Am. J. Physiol. Renal Physiol. 296, F1297–F1306 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Mayrhofer, C. et al. Alterations in fatty acid utilization and an impaired antioxidant defense mechanism are early events in podocyte injury: a proteomic analysis. Am. J. Pathol. 174, 1191–1202 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Yamamoto, T., Nakamura, T., Noble, N. A., Ruoslahti, E. & Border, W. A. Expression of transforming growth factor beta is elevated in human and experimental diabetic nephropathy. Proc. Natl Acad. Sci. USA 90, 1814–1818 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Ziyadeh, F. N. Different roles for TGF-beta and VEGF in the pathogenesis of the cardinal features of diabetic nephropathy. Diabetes Res. Clin. Pract. 82 (Suppl. 1), S38–S41 (2008).

    Article  CAS  PubMed  Google Scholar 

  77. Ziyadeh, F. N. Mediators of diabetic renal disease: the case for tgf-Beta as the major mediator. J. Am. Soc. Nephrol. 15 (Suppl. 1), S55–S57 (2004).

    Article  CAS  PubMed  Google Scholar 

  78. Ding, G., Goor, H. V., Ricardo, S. D., Orlowski, J. M. & Diamond, J. R. Oxidized LDL stimulates the expression of TGF-beta and fibronectin in human glomerular epithelial cells. Kidney Int. 51, 147–154 (1997).

    Article  CAS  PubMed  Google Scholar 

  79. Ando, T., Okuda, S., Tamaki, K., Yoshitomi, K. & Fujishima, M. Localization of transforming growth factor-beta and latent transforming growth factor-beta binding protein in rat kidney. Kidney Int. 47, 733–739 (1995).

    Article  CAS  PubMed  Google Scholar 

  80. Kreidberg, J. A. & Symons, J. M. Integrins in kidney development, function, and disease. Am. J. Physiol. Renal Physiol. 279, F233–F242 (2000).

    Article  CAS  PubMed  Google Scholar 

  81. Zhou, Y., Poczateka, M. H., Berecekb, K. H. & Murphy-Ullrich, J. E. Thrombospondin 1 mediates angiotensin II induction of TGF-β activation by cardiac and renal cells under both high and low glucose conditions. Biochem. Biophys. Res. Commun. 339, 633–641 (2005).

    Article  PubMed  CAS  Google Scholar 

  82. Annes, J. P., Munger, J. S. & Rifkin, D. B. Making sense of latent TGFbeta activation. J. Cell. Sci. 116, 217–224 (2003).

    Article  CAS  PubMed  Google Scholar 

  83. Wang, L., Sapuri-Butti, A. R., Aung, H. H., Parikh, A. N. & Rutledge, J. C. Triglyceride-rich lipoprotein lipolysis increases aggregation of endothelial cell membrane microdomains and produces reactive oxygen species. Am. J. Physiol. Heart Circ. Physiol. 295, H237–H244 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Gorin, Y. et al. Nox4 NAD(P)H oxidase mediates hypertrophy and fibronectin expression in the diabetic kidney. J. Biol. Chem. 280, 39616–39626 (2005).

    Article  CAS  PubMed  Google Scholar 

  85. Chen, S., Jim, B. & Ziyadeh, F. N. Diabetic nephropathy and transforming growth factor-beta: transforming our view of glomerulosclerosis and fibrosis build-up. Semin. Nephrol. 23, 532–543 (2003).

    Article  CAS  PubMed  Google Scholar 

  86. Chen, S. et al. The key role of the transforming growth factor-beta system in the pathogenesis of diabetic nephropathy. Ren. Fail. 23, 471–481 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. Isono, M., Chen, S., Hong, S. W., Iglesias-de la Cruz, M. C. & Ziyadeh, F. N. Smad pathway is activated in the diabetic mouse kidney and Smad3 mediates TGF-beta-induced fibronectin in mesangial cells. Biochem. Biophys. Res. Commun. 296, 1356–1365 (2002).

    Article  CAS  PubMed  Google Scholar 

  88. Choi, M. E. Mechanism of transforming growth factor-beta1 signaling: role of the mitogen-activated protein kinase. Kidney Int. 58, S53–S58 (2000).

    Article  Google Scholar 

  89. van den Berg, B. M., Vink, H. & Spaan, J. A. The endothelial glycocalyx protects against myocardial edema. Circ. Res. 92, 592–594 (2003).

    Article  CAS  PubMed  Google Scholar 

  90. Constantinescu, A. A., Vink, H. & Spaan, J. A. Endothelial cell glycocalyx modulates immobilization of leukocytes at the endothelial surface. Arterioscler. Thromb. Vasc. Biol. 23, 1541–1547 (2003).

    Article  CAS  PubMed  Google Scholar 

  91. Bondi, C. D. et al. NAD(P)H oxidase mediates TGF-beta1-induced activation of kidney myofibroblasts. J. Am. Soc. Nephrol. 21, 93–102 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Nieuwdorp, M. et al. The endothelial glycocalyx: a potential barrier between health and vascular disease. Curr. Opin. Lipidol. 16, 507–511 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. Vink, H., Constantinescu, A. A. & Spaan, J. A. Oxidized lipoproteins degrade the endothelial surface layer: implications for platelet-endothelial cell adhesion. Circulation 101, 1500–1502 (2000).

    Article  CAS  PubMed  Google Scholar 

  94. Jeansson, M. & Haraldsson, B. Morphological and functional evidence for an important role of the endothelial cell glycocalyx in the glomerular barrier. Am. J. Physiol. Renal Physiol. 290, F111–F116 (2006).

    Article  CAS  PubMed  Google Scholar 

  95. Nieuwdorp, M. et al. Endothelial glycocalyx damage coincides with microalbuminuria in type 1 diabetes. Diabetes 55, 1127–1132 (2006).

    Article  CAS  PubMed  Google Scholar 

  96. Singh, A. et al. Glomerular endothelial glycocalyx constitutes a barrier to protein permeability. J. Am. Soc. Nephrol. 18, 2885–2893 (2007).

    Article  CAS  PubMed  Google Scholar 

  97. Lusis, A. J. Atherosclerosis. Nature 407, 233–241 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. den Hartigh, L. J., Connolly-Rohrbach, J. E., Fore, S., Huser, T. R. & Rutledge, J. C. Fatty acids from very low-density lipoprotein lipolysis products induce lipid droplet accumulation in human monocytes. J. Immunol. 184, 3927–3936 (2010).

    Article  CAS  PubMed  Google Scholar 

  99. Chen, H.-C., Tan, M.-S., Tsai, J.-Y. & Lai, Y.-H. Native and oxidized low-density lipoproteins enhance superoxide production from diabetic rat glomeruli. Kidney Blood Press. Res. 23, 133–137 (2000).

    Article  PubMed  Google Scholar 

  100. Rosario, R. F. & Prabhakar, S. Lipids and diabetic nephropathy. Curr. Diab. Rep. 6, 455–462 (2006).

    Article  CAS  PubMed  Google Scholar 

  101. Forbes, J. M., Cooper, M. E., Oldfield, M. D. & Thomas, M. C. Role of advanced glycation end products in diabetic nephropathy. J. Am. Soc. Nephrol. 14, S254–S258 (2003).

    Article  CAS  PubMed  Google Scholar 

  102. D'Agati, V. & Schmidt, A. M. RAGE and the pathogenesis of chronic kidney disease. Nat. Rev. Nephrol. doi: 10.1038/nrneph.2010.54.

    Article  CAS  PubMed  Google Scholar 

  103. Zhou, L. L. et al. Accumulation of advanced oxidation protein products induces podocyte apoptosis and deletion through NADPH-dependent mechanisms. Kidney Int. 76, 1148–1160 (2009).

    Article  PubMed  CAS  Google Scholar 

  104. Hughes, A. K., Stricklett, P. K., Padilla, E. & Kohan, D. E. Effect of reactive oxygen species on endothelin-1 production by human mesangial cells. Kidney Int. 49, 181–189 (1996).

    Article  CAS  PubMed  Google Scholar 

  105. Abrass, C. K. Cellular lipid metabolism and the role of lipids in progressive renal disease. Am. J. Nephrol. 24, 46–53 (2004).

    Article  CAS  PubMed  Google Scholar 

  106. Grone, H. J., Walli, A. K. & Grone, E. F. The role of oxidatively modified lipoproteins in lipid nephropathy. Contrib. Nephrol. 120, 160–175 (1997).

    Article  CAS  PubMed  Google Scholar 

  107. Bonnet, F. & Cooper, M. E. Potential influence of lipids in diabetic nephropathy: insights from experimental data and clinical studies. Diabetes Metab. 26, 254–264 (2000).

    CAS  PubMed  Google Scholar 

  108. Perkins, B. A. et al. Regression of microalbuminuria in type 1 diabetes. N. Engl. J. Med. 348, 2285–2293 (2003).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to John C. Rutledge.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rutledge, J., Ng, K., Aung, H. et al. Role of triglyceride-rich lipoproteins in diabetic nephropathy. Nat Rev Nephrol 6, 361–370 (2010). https://doi.org/10.1038/nrneph.2010.59

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneph.2010.59

This article is cited by

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