Renoprotection by Rosiglitazone in Accelerated Type 2 Diabetic Nephropathy: Role of STAT1 Inhibition and Nephrin Restoration

• Published in: American journal of nephrology Vol. 32; no. 2; pp. 145 - 155
• Main Authors: Tang, Sydney C.W., Leung, Joseph C.K., Chan, Loretta Y.Y., Cheng, Amy Shan, Lan, Hui Yao, Lai, Kar Neng
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland S. Karger AG 01.01.2010
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Cytokines - antagonists & inhibitors; Cytokines - metabolism; Diabetes Mellitus, Type 2 - complications; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Diabetic Nephropathies - prevention & control; Disease Models, Animal; Down-Regulation - drug effects; Kidney - metabolism; Kidney - pathology; Kidney Glomerulus - drug effects; Kidney Glomerulus - metabolism; Kidney Glomerulus - pathology; Male; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; Mice; Mice, Inbred C57BL; Nephrectomy; Original Report: Laboratory Investigation; Protective Agents - pharmacology; STAT1 Transcription Factor - antagonists & inhibitors; STAT1 Transcription Factor - metabolism; Thiazolidinediones - pharmacology; Uninephrectomy; Rosiglitazone; Diabetic nephropathy; Nephrin; STAT1; db/db mouse
• ISSN: 0250-8095; 1421-9670
• DOI: 10.1159/000316056

Background: Rosiglitazone (Ros) has been shown to attenuate CXCL8 and ICAM-1 overexpression in renal tubular cells exposed to glycated albumin. The present study explores whether this can be translated into renoprotection in vivo. Uninephrectomized (Unx) type 2 diabetic db/db mice were chosen as a model of accelerated diabetic nephropathy. Methods: Uninephrectomy was performed in 10-week-old db/db mice. They were then treated with vehicle, metformin or Ros for 8 weeks. Results: Unx-db/db mice treated with Ros had lower serum creatinine and albuminuria, less severe glomerulosclerosis, tubulointerstitial injury, fewer infiltrating macrophages, and less proliferating nuclear antigen-positive tubular cells compared with mice treated with metformin that had a similar level of glycemic control and insulin resistance. In addition, Ros but not metformin attenuated renal cortical expression of CCL2, MIP-2, and ICAM-1 and inhibited p-STAT1 signal activation. Ros also increased glomerular nephrin expression. Conclusions: Our results delineated the biochemical and histologic characteristics of Unx-db/db mice and demonstrated the in vivo glucose-independent anti-inflammatory mechanisms of Ros in nephropathy of accelerated murine type 2 diabetes.