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This Article Full Text Full Text (PDF) All Versions of this Article: 295/5/E1205    most recent 90534.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sen, U. Articles by Tyagi, S. C. Search for Related Content PubMed PubMed Citation Articles by Sen, U. Articles by Tyagi, S. C.

Ciglitazone, a PPAR agonist, ameliorates diabetic nephropathy in part through homocysteine clearance

Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, Kentucky

Submitted 23 June 2008 ; accepted in final form 2 September 2008

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 wk of treatment; only 12- and 16-wk animals received CZ in drinking water after a 10-wk alloxan treatment. In diabetes, PPAR cDNA, mRNA, and protein expression were repressed, whereas an increase in plasma and glomerular Hcy levels was observed. CZ normalized PPAR mRNA and protein expression and glomerular level of Hcy, whereas plasma level of Hcy remained unchanged. GFR was dramatically increased at 1-wk diabetic induction, followed by hypofiltration at 10 wk, and was normalized by CZ treatment. This result corroborated with glomerular and preglomerular arteriole histology. A steady-state increase of RVR in diabetic 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.

peroxisome proliferator-activated receptor-; matrix metalloproteinase; tissue inhibitor of metalloproteinases; glomerulosclerosis

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