Antifibrotic effects of pioglitazone on the kidney in a rat model of type 2 diabetes mellitus.
BACKGROUND
Recent evidence suggests that treatment of type 2 diabetes with thiazolidinediones [peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists], ameliorates glomerulosclerosis and tubulointerstitial fibrosis in the rat kidney. In the current work, we have investigated whether these drugs, and specifically pioglitazone (PGT), act by preventing fibrosis and kidney dysfunction mainly through antioxidant and anti-inflammatory effects, independently of glycaemic control.


METHODS
Male 2- to 3-month-old obese Zucker fa/fa (OZR) and ZDF fa/fa rats (ZDFR), and their control the lean Zucker rat (LZR), were used. Diabetic rats were given either a low dose (0.6 mg/kg/day) or a high dose (12 mg/ kg/day) of PGT in the chow for 2 or 4-5 months. Glycaemia, blood pressure, creatinine clearance and proteinuria were determined, and the underlying histopathology was defined with markers of fibrosis, glomerular damage, oxidative stress and inflammation by immunohistochemistry/ quantitative image analysis in tissue sections, and western blots and ad hoc assays in fresh tissue.


RESULTS
PGT at low doses given for 4-5 months considerably reduced blood pressure, proteinuria and creatinine clearance. This was associated with amelioration of renal tissue damage and fibrosis, evidenced by the glomerulosclerosis, tubulointerstitial fibrosis, tubular atrophy and podocyte injury indexes, and of oxidative stress and inflammation, as shown by the decrease in the respective markers, although glycaemia remained high and obesity was not affected.


CONCLUSIONS
These results indicate that low doses of PGT ameliorate renal fibrosis and preserve renal function in this animal model of metabolic syndrome, independently of glycaemic control or effects on body weight.
Toblli
Jorge E
JE
Laboratory of Experimental Medicine, Hospital Alemán, Buenos Aires, Argentina.
Ferrini
Monica G
MG
Cao
Gabriel
G
Vernet
Dolores
D
Angerosa
Margarita
M
Gonzalez-Cadavid
Nestor F
NF
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000473:pathology; D005355:Fibrosis / Q000517:prevention & control; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007249:Inflammation / Q000517:prevention & control; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007677:Kidney Function Tests; D007684:Kidney Tubules / Q000473:pathology*; D008297:Male; D009765:Obesity / Q000188:drug therapy* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D000077205:Pioglitazone; D051381:Rats; D011924:Rats, Zucker; D045162:Thiazolidinediones / Q000627:therapeutic use*
D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077205:Pioglitazone