Antifibrotic effects of pioglitazone at low doses on the diabetic rat kidney are associated with the improvement of markers of cell turnover, tubular and endothelial integrity, and angiogenesis.

Abstract

BACKGROUND/AIMS:

Pioglitazone and other thiazolidinediones are renoprotective in diabetic nephropathy at doses that normalize glycemia, presumably as a consequence of glycemic control. However, low doses of pioglitazone that did not normalize glycemia in rat models of type 2 diabetes prevented tubulointerstitial fibrosis and glomerulosclerosis through counteracting inflammation, oxidative stress, cell cycle arrest, and fibrosis. The current work tested whether this low-dose treatment also reduces other fibrosis and inflammation factors in the diabetic kidney and prevents tubular cell loss, endothelial damage, and abnormal angiogenesis.

METHODS:

ZDF fa/fa rats (ZDF) were fed for 4 months chow with 0.001% pioglitazone, and the untreated ZDF and the non-diabetic lean Zucker rats (LZR) received regular chow. Proteinuria, creatinine clearance, blood pressure, and renal quantitative histopathology markers were determined.

RESULTS:

Correction of renal function in ZDF by pioglitazone, occurring with a glycemia >250 mg/dl, was accompanied by normalization of the renal levels of connective tissue growth factor and fibronectin (fibrosis), TNF-α, interleukin-6 and MCP-1 (inflammation), megalin (tubular cells), the PCNA/caspase-3 ratio (positive cell turnover), VEGF (abnormal angiogenesis), and the ratio between eNOS and iNOS (endothelial dysfunction).

CONCLUSION:

This supports mechanisms for the renoprotective effects of pioglitazone in diabetes additional to glycemic control.

• Authors: Jorge E Toblli, Gabriel Cao, Jorge F Giani, Margarita Angerosa, Fernando P Dominici, Nestor F Gonzalez-Cadavid
• Journal: Kidney & blood pressure research (Kidney Blood Press Res) Vol. 34 Issue 1 Pg. 20-33 ( 2011) ISSN: 1423-0143 [Electronic] Switzerland
• PMID: 21071958 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 S. Karger AG, Basel.

Chemical References

• Antifibrinolytic Agents
• Biomarkers
• Thiazolidinediones
• Pioglitazone

Topics

• Animals
• Antifibrinolytic Agents (pharmacology, therapeutic use)
• Biomarkers (metabolism)
• Diabetes Mellitus, Type 2 (drug therapy, metabolism, pathology)
• Diabetic Nephropathies (drug therapy, metabolism, pathology)
• Dose-Response Relationship, Drug
• Endothelium, Vascular (cytology, drug effects, metabolism)
• Kidney Tubules (cytology, drug effects, metabolism)
• Male
• Neovascularization, Physiologic (drug effects, physiology)
• Pioglitazone
• Rats
• Rats, Zucker
• Thiazolidinediones (pharmacology, therapeutic use)