title: Ciglitazone, a PPARgamma agonist, ameliorates diabetic nephropathy in part through homocysteine clearance.
abstract: 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.
authors.affiliation: Department of Physiology and Biophysics, University of Louisville, Louisville, Kentucky 40202, USA. u0sen001@louisville.edu
authors.forename: Utpal
authors.initials: U
authors.lastname: Sen
authors.forename: Walter E
authors.initials: WE
authors.lastname: Rodriguez
authors.forename: Neetu
authors.initials: N
authors.lastname: Tyagi
authors.forename: Munish
authors.initials: M
authors.lastname: Kumar
authors.forename: Soumi
authors.initials: S
authors.lastname: Kundu
authors.forename: Suresh C
authors.initials: SC
authors.lastname: Tyagi
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D004837:Epinephrine / Q000031:analogs & derivatives / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006710:Homocysteine / Q000097:blood / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D012077:Renal Artery / Q000187:drug effects / Q000502:physiology; D012079:Renal Circulation / Q000187:drug effects / Q000502:physiology; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D000097792:Tissue Inhibitor of Metalloproteinase-4
chemical_list: D001786:Blood Glucose; D004837:Epinephrine; D006710:Homocysteine; D007004:Hypoglycemic Agents; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D009569:Nitric Oxide; D047495:PPAR gamma; D045162:Thiazolidinediones; D019715:Tissue Inhibitor of Metalloproteinase-1; D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4; C039671:ciglitazone
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