Peroxisome proliferator-activated receptors (PPARs) are a new family of ligand-activated nuclear receptors originally described as mediators of adipocyte growth and differentiation. PPAR-gamma has been found to be the target of action of thiazolidinediones, a newly developed group of insulin-sensitizing antidiabetic agents used in the treatment of noninsulin- dependent diabetes mellitus (NIDDM). Recent studies have shown that PPAR-gamma activation by thiazolidinediones or prostaglandin J2 has profound effects on cytokine and extracellular matrix proteinase expression in macrophages and vascular smooth muscle, respectively. Nephropathy leading to end-stage disease is an cause of morbidity and mortality in NIDDM. In these patients, thiazolidinediones reduce albuminuria by mechanisms independent of their glucose-lowering action. Our preliminary studies demonstrate the presence of PPAR-gamma in glomerular mesangial cells. Moreover, PPAR-gamma levels are modulated by TNFalpha, a cytokine that causes insulin resistance. In addition, PPAR-gamma activators inhibit cytokine stimulation of inducible NO synthase (iNOS). The purpose of this pilot and feasibility program is to characterize and investigate the actions of PPAR-gamma in mesangial cells. The main hypothesis is that PPAR-gamma modulates cytokine action in mesangial cells. We also propose that cytokines that cause insulin resistance (e.g. TNFalpha) modulate renal PPAR-gamma activity. We propose to study the following specific aims: (1) to investigate the effects of PPAR-gamma activation on cytokine-stimulated iNOS expression and activity in mesangial cells, (2) to determine the role of heme oxygenase-1 on PPAR-gamma-induced iNOS inhibition, and (3) to determine the effects of TNFalpha on mesangial cell PPAR-gamma expression and activity. This pilot program addresses a novel and important area of research in diabetes and its renal complications. Elucidation of the actions of PPAR-gamma in mesangial cells and the effects of thiazolidinedione drugs on renal cytokine expression and function is likely to contribute important information for future research on the pathogenesis and treatment of diabetic nephropathy.
