A novel STAT3 inhibitor, S3I-201, attenuates renal interstitial fibroblast activation and interstitial fibrosis in obstructive nephropathy.
Accumulation of both interstitial myofibroblasts and excessive production of extracellular matrix proteins is a common pathway contributing to chronic kidney disease. In a number of tissues, activation of STAT3 (signal transducer and activator of transcription 3) increases expression of multiple profibrotic genes. Here, we examined the effect of a STAT3 inhibitor, S3I-201, on activation of renal interstitial fibroblasts and progression of renal fibrosis. Treatment of cultured rat renal interstitial fibroblasts with S3I-201 inhibited their activation, as evidenced by dose- and time-dependent blockade of alpha-smooth muscle actin and fibronectin expression. In a mouse model of renal interstitial fibrosis induced by unilateral ureteral obstruction, STAT3 was activated, and administration of S3I-201 attenuated both this activation and extracellular matrix protein deposition following injury. S3I-201 reduced infiltration of the injured kidney by inflammatory cells and suppressed the injury-induced expression of fibronectin, alpha-smooth muscle actin, and collagen type-1 proteins, as well as the expression of multiple cytokines. Furthermore, S3I-201 inhibited proliferation and induced apoptosis preferentially in renal interstitial fibroblasts of the obstructed kidney. Thus, our results suggest that increased STAT3 activity mediates activation of renal interstitial fibroblasts and the progression of renal fibrosis. Inhibition of STAT3 signaling with S3I-201 may hold therapeutic potential for fibrotic kidney diseases.
Pang
Maoyin
M
Department of Medicine, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA.
Ma
Li
L
Gong
Rujun
R
Tolbert
Evelyn
E
Mao
Haiping
H
Ponnusamy
Murugavel
M
Chin
Y Eugene
YE
Yan
Haidong
H
Dworkin
Lance D
LD
Zhuang
Shougang
S
D000636:Aminosalicylic Acids / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001557:Benzenesulfonates / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis / Q000378:metabolism; D007674:Kidney Diseases / Q000378:metabolism / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009395:Nephritis, Interstitial / Q000378:metabolism / Q000473:pathology; D051381:Rats; D051436:Renal Insufficiency, Chronic / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014517:Ureteral Obstruction / Q000378:metabolism / Q000473:pathology*
D000636:Aminosalicylic Acids; D001557:Benzenesulfonates; D016326:Extracellular Matrix Proteins; C520337:NSC 74859; D050796:STAT3 Transcription Factor