Renoprotection by rosiglitazone in accelerated type 2 diabetic nephropathy: Role of STAT1 inhibition and nephrin restoration.
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.
Tang
Sydney C W
SC
Department of Medicine, Queen Mary Hospital, University of Hong Kong, SAR, China. scwtang@hkucc.hku.hk
Leung
Joseph C K
JC
Chan
Loretta Y Y
LY
Cheng
Amy Shan
AS
Lan
Hui Yao
HY
Lai
Kar Neng
KN
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009392:Nephrectomy; D020011:Protective Agents / Q000494:pharmacology*; D000077154:Rosiglitazone; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D008565:Membrane Proteins; D020011:Protective Agents; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D045162:Thiazolidinediones; C113267:nephrin; D000077154:Rosiglitazone