nsc-74859 and Renal-Insufficiency--Chronic

Kidney fibrosis is a histological hallmark of chronic kidney disease (CKD), where hyperuricemia is a key independent risk factor. Considerable evidence indicated that STAT3 is one of the crucial signaling pathways in the progression of kidney fibrosis. Here, we investigated that pharmacological blockade of STAT3 delayed the progression of renal fibrosis in hyperuricemia-induced CKD.. In the study, we used the mixture of adenine and potassium oxonate to perform kidney injury and fibrosis in hyperuricemic mice, accompanied by STAT3 activation in tubular and interstitial cells.. Treatment with STAT3 inhibitor S3I-201 improved renal dysfunction, reduced serum uric acid level, and delayed the progression of kidney fibrosis. Furthermore, S3I-201 could suppress fibrotic signaling pathway of TGF-β/Smads, JAK/STAT and NF-κB, as well as inhibit the expression of multiple profibrogenic cytokines/chemokines in the kidneys of hyperuricemic mice.. These data suggested that STAT3 inhibition was a potent anti-fibrotic strategy in hyperuricemia-related CKD.

Topics: Aminosalicylic Acids; Animals; Benzenesulfonates; Disease Models, Animal; Fibrosis; Hyperuricemia; Kidney; Male; Mice; Mice, Inbred C57BL; Phosphorylation; Renal Insufficiency, Chronic; STAT3 Transcription Factor; Uric Acid

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