PMID- 18780770 OWN - NLM STAT- MEDLINE DCOM- 20090112 LR - 20231213 IS - 0193-1849 (Print) IS - 1522-1555 (Electronic) IS - 0193-1849 (Linking) VI - 295 IP - 5 DP - 2008 Nov TI - Ciglitazone, a PPARgamma agonist, ameliorates diabetic nephropathy in part through homocysteine clearance. PG - E1205-12 LID - 10.1152/ajpendo.90534.2008 [doi] AB - Diabetes and hyperhomocysteinemia (HHcy) are two independent risk factors for glomeruloslerosis and renal insufficiency. Although PPARgamma 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 PPARgamma 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, PPARgamma cDNA, mRNA, and protein expression were repressed, whereas an increase in plasma and glomerular Hcy levels was observed. CZ normalized PPARgamma 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 PPARgamma and clearing glomerular tissue Hcy. FAU - Sen, Utpal AU - Sen U AD - Department of Physiology and Biophysics, University of Louisville, Louisville, Kentucky 40202, USA. u0sen001@louisville.edu FAU - Rodriguez, Walter E AU - Rodriguez WE FAU - Tyagi, Neetu AU - Tyagi N FAU - Kumar, Munish AU - Kumar M FAU - Kundu, Soumi AU - Kundu S FAU - Tyagi, Suresh C AU - Tyagi SC LA - eng GR - HL-71010/HL/NHLBI NIH HHS/United States GR - HL-74185/HL/NHLBI NIH HHS/United States GR - HL-88012/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20080909 PL - United States TA - Am J Physiol Endocrinol Metab JT - American journal of physiology. Endocrinology and metabolism JID - 100901226 RN - 0 (Blood Glucose) RN - 0 (Hypoglycemic Agents) RN - 0 (PPAR gamma) RN - 0 (Thiazolidinediones) RN - 0 (Tissue Inhibitor of Metalloproteinase-1) RN - 0 (Tissue Inhibitor of Metalloproteinases) RN - 0LVT1QZ0BA (Homocysteine) RN - 31C4KY9ESH (Nitric Oxide) RN - EC 3.4.24.24 (Matrix Metalloproteinase 2) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) RN - U8QXS1WU8G (ciglitazone) RN - YKH834O4BH (Epinephrine) SB - IM MH - Animals MH - Blood Glucose/metabolism MH - Diabetes Mellitus, Experimental/blood/drug therapy/physiopathology MH - Diabetic Nephropathies/blood/*drug therapy/physiopathology MH - Epinephrine/analogs & derivatives/pharmacology MH - Gene Expression/drug effects MH - Glomerular Filtration Rate/drug effects MH - Homocysteine/blood/*metabolism MH - Hypoglycemic Agents/pharmacology/therapeutic use MH - Kidney Tubules/drug effects/metabolism/pathology MH - Male MH - Matrix Metalloproteinase 2/metabolism MH - Matrix Metalloproteinase 9/metabolism MH - Mice MH - Mice, Inbred C57BL MH - Nitric Oxide/metabolism MH - PPAR gamma/agonists/genetics/*metabolism MH - Renal Artery/drug effects/physiology MH - Renal Circulation/drug effects/physiology MH - Thiazolidinediones/*pharmacology/therapeutic use MH - Tissue Inhibitor of Metalloproteinase-1/metabolism MH - Tissue Inhibitor of Metalloproteinases/metabolism MH - Vascular Resistance/drug effects/physiology MH - Vasoconstriction/drug effects/physiology MH - Tissue Inhibitor of Metalloproteinase-4 PMC - PMC2584817 EDAT- 2008/09/11 09:00 MHDA- 2009/01/13 09:00 PMCR- 2009/11/01 CRDT- 2008/09/11 09:00 PHST- 2008/09/11 09:00 [pubmed] PHST- 2009/01/13 09:00 [medline] PHST- 2008/09/11 09:00 [entrez] PHST- 2009/11/01 00:00 [pmc-release] AID - 90534.2008 [pii] AID - E-90534-2008 [pii] AID - 10.1152/ajpendo.90534.2008 [doi] PST - ppublish SO - Am J Physiol Endocrinol Metab. 2008 Nov;295(5):E1205-12. doi: 10.1152/ajpendo.90534.2008. Epub 2008 Sep 9.