Pharmaceutical agonists of peroxisome proliferator-activated receptors (PPARs) are widely used in the management of type 2 diabetes, chiefly as lipid-lowering agents and oral hypoglycaemic agents. Although most of the focus has been placed on their cardiovascular effects, both positive and negative, these agents also have significant renoprotective actions in the diabetic kidney. Over and above action on metabolic control and effects on blood pressure, PPAR agonists also appear to have independent effects on a number of critical pathways that are implicated in the development and progression of diabetic kidney disease, including oxidative stress, inflammation, hypertrophy, and podocyte function. This review will examine these direct and indirect actions of PPAR agonists in the diabetic kidney and explore recent findings of clinical trials of PPAR agonists in patients with diabetes. 1. Introduction Pharmaceutical agonists of peroxisome proliferator-activated receptors (PPARs) are widely used in the management of type 2 diabetes. PPARα agonists, known as fibrates, have been used for over 40 years in patients with diabetes, chiefly as lipid-lowering agents. Over the last decade, PPARγ agonists, known as thiazolidinediones (TZDs) or glitazones, have also come into clinical use as oral hypoglycaemic agents. Selective agonists of a third isoform of PPAR, PPAR β/δ are also under clinical development for treatment of the metabolic syndrome [1]. Although most focus has been placed on their metabolic and cardiovascular effects, these agents also have direct and indirect actions in the diabetic kidney. Such actions are potentially important as the presence and severity of kidney disease adversely affects the well being of individuals with diabetes and significantly contributes to disease morbidity and increases their risk of a premature death. For example, we have shown that in Finnish adults with type 1 diabetes excess mortality associated with diabetes is almost entirely confined to those with chronic kidney disease (CKD) [2]. Equally, in patients with type 2 diabetes, kidney disease is associated with an increase in the risk of death [3, 4]. Consequently, long-term benefits from preventing and managing diabetic kidney disease may prove to be among the most important actions of these agents. This review will examine the indirect and direct actions of PPAR agonists specifically in the diabetic kidney and explore recent findings of clinical trials of PPAR agonists in patients with diabetes. 2. The Expression of PPARs in the Kidney PPARs are ligand-activated
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