Pioglitazone mitigates renal glomerular vascular changes in high-fat, high-calorie-induced type 2 diabetes mellitus.
Our hypothesis is that impairment of peroxisome proliferator-activated receptor-gamma (PPARgamma) initiates renal dysfunction by increasing renal glomerular matrix metalloproteinase-2 (MMP-2) activity because of increased renal homocysteine (Hcy) and decreased nitric oxide (NO) levels. C57BL/6J mice were made diabetic (D) by being fed a high-fat-calorie diet, and an increase in PPARgamma activity was induced by adding pioglitazone (Pi) to the diet. Mice were grouped as follows: normal calorie diet (N), D, N+Pi, and D+Pi (n = 6/group). The glomerular filtration rate (GFR), renal artery blood flow and pressure, and plasma glucose were measured. Renal glomeruli and preglomerular arterioles were isolated. Plasma and glomerular levels of NO, Hcy, and MMP activity were measured. The contractile response to phenylephrine and the dilatation response to acetylcholine in renal arteriolar rings were measured in a tissue myobath. In N, D, N+Pi, and D+Pi groups, respectively, GFR was 9.4 +/- 1.2, 3.9 +/- 1.1, 9.2 +/- 1.6, and 8.4 +/- 1.4 microl x min(-1) x g body wt(-1). Renovascular resistance was 140 +/- 3, 367 +/- 21, 161 +/- 9, and 153 +/- 10 mmHg x ml x min(-1). Levels of Hcy were increased from 5.8 +/- 1.5 in the N to 18.0 +/- 4.0 micromol/l in the D group. Glomerular levels of MMP-2 were increased in D mice compared with N mice, and there was no change in levels of MMP-9. Treatment with Pi ameliorated glomerular levels of MMP-2 and Hcy in the D group. Renal artery ring contraction and relaxation by phenylephrine and acetylcholine, respectively, were attenuated in the D groups compared with the N groups. Results suggest that a PPARgamma agonist ameliorates preglomerular arteriole remodeling in diabetes by decreasing tissue levels of Hcy and MMP-2 activity and increasing NO.
Rodriguez
Walter E
WE
Department of Physiology and Biophysics, University of Louisville School of Medicine, A-1115, 500 South Preston St., Louisville, KY 40202, USA.
Tyagi
Neetu
N
Joshua
Irving G
IG
Passmore
John C
JC
Fleming
John T
JT
Falcone
Jeff C
JC
Tyagi
Suresh C
SC
D000818:Animals; D001160:Arterioles / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000473:pathology; D004041:Dietary Fats / Q000494:pharmacology; D006439:Hemodynamics; D006710:Homocysteine / Q000097:blood; D007678:Kidney Glomerulus / Q000098:blood supply / Q000187:drug effects* / 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; D018384:Oxidative Stress / Q000502:physiology; D010656:Phenylephrine / Q000494:pharmacology; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use*
D001786:Blood Glucose; D004041:Dietary Fats; D045162:Thiazolidinediones; D006710:Homocysteine; D010656:Phenylephrine; D009569:Nitric Oxide; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D000077205:Pioglitazone