Are partial PPAR gamma agonists a rational therapeutic strategy for preventing abnormalities of the diabetic kidney

Abstract

Diabetes mellitus is probably the single most important metabolic disease and is widely recognized as one of the leading causes of death and disability. Up to a third of people with diabetes mellitus suffer end-stage renal failure due to diabetic nephropathy. Diabetic nephropathy strategies to delay progression of diabetic nephropathy- including glycemic and blood pressure control, modification of the rennin-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. Peroxisome proliferator-activated receptors (PPAR) are members of the nuclear hormone receptor superfamily of ligand- activated transcription factors. PPAR-γ is the key regulator of lipid metabolism and energy balance implicated in the development of insulin resistance. The identification of putative natural and synthetic ligands and activators of PPAR-γ has helped to unravel the molecular basis of its function, including molecular details regarding ligand binding, conformational changes of the receptor and cofactor binding leading to the emergence of the concept of selective PPAR-γ modulators .No satisfactory therapeutic option is currently available to treat patients with nephropathy except for fewer agents like angiotensin converting enzyme inhibitors, angiotensin AT1 receptor blockers and few antioxidants, which have been shown to improve the function of diabetic kidney to some extent. Thus, tremendous efforts are being made to explore promising therapeutic interventions to treat diabetic nephropathy. This review discussed various presently employed and recently developed pharmacological interventions to treat diabetic nephropathy and to improve the function of diabetic kidney. In addition, the recently identified potential target sites involved in the pathogenesis of diabetic nephropathy have been delineated.