Are PPAR alpha agonists a rational therapeutic strategy for preventing abnormalities of the diabetic kidney?

Abstract

The uncontrolled diabetes mellitus may result in the induction of diabetic nephropathy, one of the detrimental microvascular complications of diabetes mellitus. Diabetic nephropathy is associated with glomerular hypertrophy, glomerulosclerosis, tubulointerstitial fibrosis, mesangial cell expansion, followed by albuminuria and reduction in glomerular filtration rate. Indeed, no promising therapeutic options are available in the present clinical scenario to manage efficiently the diabetic nephropathy. Nevertheless, angiotensin converting enzyme inhibitors and angiotensin-II-AT1 receptor blockers are currently employed to improve structural and functional status of the diabetic kidney. These interventions, however, are not optimal in improving overall outcomes of diabetic nephropathy. Hence, there is a continuing need of developing promising therapeutic interventions to manage this insidious condition adequately. Recent bench and clinical studies strongly suggest the potentials of peroxisome proliferator-activated receptor alpha (PPARα) agonists in the management of diabetic nephropathy by keeping the view that renal lipid accumulation-induced lipotoxicity is one of risk factors for nephropathy during chronic diabetes mellitus. As inflammation, oxidative stress and dyslipidemia are common consequences of renal dysfunction, PPARα agonists could serve as promising therapeutic agents for controlling the progression of diabetic nephropathy. In fact, fenofibrate, a hypolipidemic agent acts as a PPARα agonist, reduced renal lipotoxicity, inflammation, fibrosis and oxidative stress, and subsequently prevented the symptoms of diabetic nephropathy. However, fenofibrate has been shown to cause renal dysfunction in established renal disorders. The present review addressed the rationale of employing PPARα agonists in the management of diabetic nephropathy.