nsc-74859 and Kidney-Diseases

Hypertension adversely affects the kidney and is the second leading cause of kidney failure. Overproduction of angiotensin II greatly contributes to the progression of hypertensive kidney disease. Angiotensin II has recently been shown to activate STAT3 in cardiovascular cells. However, the underlying mechanisms of STAT3 activation by angiotensin II and downstream functional consequences in the kidneys are not fully understood.. C57BL/6 mice were treated with angiotensin II by subcutaneous infusion for 1 month to develop nephropathy. Mice were treated with either adeno-associated virus expressing STAT3 shRNA or STAT3 inhibitor, S3I-201. Human archival kidney samples from five patients with hypertension and five individuals without hypertension were also examined. In vitro, STAT3 was blocked using siRNA or STAT3 inhibitor S3I-201 in the renal proximal tubular cell line, NRK52E, after exposure to angiotensin II.. Angiotensin II activated STAT3 in kidney epithelial cells through engaging toll-like receptor 4 (TLR4) and JAK2, which was independent of IL-6/gp130 and angiotensin AT. Our study reveals a novel mechanism of STAT3 activation, induced by angiotensin II, in kidney tissues and highlights a translational significance of a STAT3 inhibitor as potential therapeutic agent for hypertensive kidney disease.

Topics: Aminosalicylic Acids; Angiotensin II; Animals; Benzenesulfonates; Cells, Cultured; Disease Models, Animal; Fibrosis; Humans; Hypertension, Renal; Infusions, Subcutaneous; Kidney Diseases; Mice; Mice, Inbred C57BL; Nephritis; RNA, Small Interfering; STAT3 Transcription Factor; Toll-Like Receptor 4

Topics: Aminosalicylic Acids; Animals; Benzenesulfonates; Fibronectins; Fibrosis; Kidney; Kidney Diseases; Male; Matrix Metalloproteinase 9; Mesenchymal Stem Cells; Rats, Sprague-Dawley; STAT3 Transcription Factor; Ureteral Obstruction

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.

Topics: Aminosalicylic Acids; Animals; Benzenesulfonates; Cell Line; Cells, Cultured; Disease Models, Animal; Extracellular Matrix Proteins; Fibroblasts; Fibrosis; Kidney Diseases; Kidney Failure, Chronic; Male; Mice; Mice, Inbred C57BL; Nephritis, Interstitial; Rats; Renal Insufficiency, Chronic; STAT3 Transcription Factor; Ureteral Obstruction