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Drug Insight: thiazolidinediones and diabetic nephropathy—relevance to renoprotection

Nature Clinical Practice Nephrology volume 1, pages 33–43 (2005)Cite this article

Abstract

Up to a third of people with diabetes mellitus suffer end-stage renal failure due to diabetic nephropathy. Strategies to delay progression of diabetic nephropathy—including glycemic and blood pressure control, modification of the renin–angiotensin system and management of lipid levels with statins—have been effective, but development of new strategies is essential if the ever-increasing burden of this disease is to be minimized. Thiazolidinediones (TZDs) are a family of compounds used as oral hypoglycemic agents in patients with type 2 diabetes mellitus. The therapeutic effects of TZDs are largely a function of their activity as ligands of peroxisome proliferator-activated receptor gamma (PPARγ), a transcription factor that has a central role in adipogenesis and insulin sensitization. In vitro animal and clinical studies have shown that TZDs ameliorate symptoms and pathogenic mechanisms of diabetic and nondiabetic nephropathy, including proteinuria, excessive deposition of glomerular matrix, cellular proliferation, inflammation and fibrosis. Many of these favorable effects occur under both normal and high-glucose conditions. The mechanisms responsible probably involve both PPARγ-dependent and PPARγ-independent pathways. So, TZDs and other agonists of PPARγ offer promise for treatment of diabetic nephropathy; however, before their putative renoprotective effects can be translated into clinical practice, the complex mechanisms of PPARγ activity and regulation will need to be investigated further.

Key Points

  • Thiazolidinediones (TZDs) are agonists of peroxisome proliferator-activated receptors (PPARs)

  • PPARs are expressed in the kidney, and have prominent roles in insulin sensitization and adipogenesis

  • TZDs (e.g. pioglitazone and rosiglitazone) are used as oral hypoglycemic agents in type 2 diabetes mellitus

  • Agonists of PPARγ, including TZDs, ameliorate tubulointerstitial fibrosis, albuminuria and glomerulosclerosis in models of diabetic and nondiabetic nephropathy

  • Early trials in humans with diabetic nephropathy have shown that TZDs ameliorate albuminuria and confer cardiovascular benefits

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Figure 1: Molecular mechanisms of diabetic nephropathy.
Figure 2: Thiazolidinediones and activation of peroxisome proliferator-activated receptors.
Figure 3: Potential renoprotective effects of agonists of peroxisome proliferator-activated receptors.

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Acknowledgements

We thank E Kantzow for her assistance with the literature search. We acknowledge the support of the National Health and Medical Research Council of Australia, Juvenile Diabetes Research Foundation and Merck Laboratories for generously providing us with L805645.

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Authors and Affiliations

  1. Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia

    Usha Panchapakesan & Xin-Ming Chen

  2. Senior Research Scientist,

    Usha Panchapakesan & Xin-Ming Chen

  3. a Senior Nephrologist, Professor of Medicine and Research Chairperson at Royal North Shore Hospital, Sydney, Australia

    Carol A Pollock

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Correspondence to Carol A Pollock.

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Panchapakesan, U., Chen, XM. & Pollock, C. Drug Insight: thiazolidinediones and diabetic nephropathy—relevance to renoprotection. Nat Rev Nephrol 1, 33–43 (2005). https://doi.org/10.1038/ncpneph0029

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