Diabetes and hyperhomocysteinemia (HHcy) are two independent risk factors for glomeruloslerosis and renal insufficiency. Although PPAR agonists, such as ciglitazone (CZ), are known to modulate diabetic nephropathy, the role of CZ in diabetes-associated HHcy and renopathy is incompletely defined. We tested the hypothesis that induction of PPAR by CZ decreases tissue Hcy level; this provides a protective role against diabetic nephropathy. C57BL/6J mice were administered alloxan to create diabetes. Mice were grouped to 0, 1, 10, 12 and 16 weeks of treatment; only 12 and 16 weeks animals received CZ in drinking water after a 10-week alloxan treatment. In diabetes, PPAR cDNA, mRNA and protein expression were repressed, whereas, an increase in plasma and glomerular Hcy levels were observed. CZ normalized PPAR mRNA and protein expression, glomerular level of Hcy, whereas, plasma level of Hcy remained unchanged. GFR was dramatically increased at 1-week diabetic induction followed by hypofiltration at 10 weeks and was normalized by CZ treatment. This result corroborated with glomerular and preglomerular arteriole histology. A steady state increase of RVR in diabetec mice became normal with CZ treatment. CZ ameliorated decrease bioavailability of NO in the diabetic animal. Glomerular MMP-2 and MMP-9 activities as well as TIMP-1 expression were increased robustly in diabetic mice and normalized with CZ treatment. Interestingly, TIMP-4 expression was opposite to that of TIMP-1 in diabetic and CZ-treated groups. These results suggested that diabetic nephropathy exacerbated glomerular tissue level of Hcy, and this caused further deterioration of glomerulus. CZ, however, protected diabetic nephropathy; in part, by activating PPAR and clearing glomerular tissue Hcy.