Abstract
Renal tubulointerstitial lesions (TILs), a common pathologic hallmark of chronic kidney disease that evolves to end-stage renal disease, is characterized by progressive inflammation and pronounced fibrosis of the kidney. However, current therapeutic approaches to treat these lesions remain largely ineffectual. Previously, we demonstrated that elevated IL-36α levels in human renal tissue and urine are implicated in impaired renal function, and IL-36 signaling enhances activation of NLRP3 inflammasome in a mouse model of TILs. Recently, we synthesized NSC828779, a salicylanilide derivative (protected by U.S. patents with US 8975255 B2 and US 9162993 B2), which inhibits activation of NF-κB signaling with high immunomodulatory potency and low IC50, and we hypothesized that it would be a potential drug candidate for renal TILs. The current study validated the therapeutic effects of NSC828779 on TILs using a mouse model of unilateral ureteral obstruction (UUO) and relevant cell models, including renal tubular epithelial cells under mechanically induced constant pressure. Treatment with NSC828779 improved renal lesions, as demonstrated by dramatically reduced severity of renal inflammation and fibrosis and decreased urinary cytokine levels in UUO mice. This small molecule specifically inhibits the IL-36α/NLRP3 inflammasome pathway. Based on these results, the beneficial outcome represents synergistic suppression of both the IL-36α-activated MAPK/NLRP3 inflammasome and STAT3- and Smad2/3-dependent fibrogenic signaling. NSC828779 appears justified as a new drug candidate to treat renal progressive inflammation and fibrosis.
Highlights
Renal tubulointerstitial lesions (TILs), characterized by inflammation and fibrosis of the kidneys, are key pathological findings underlying progression to end-stage renal disease [1,2]
IL-1β secretion and caspase-1 activation in recombinant IL-36α (rIL-36α)-primed renal tubular epithelial cell (TEC) (Figure 4D). These results suggest that NSC828779 reduces rIL-36α-meditated NLRP3 inflammasome activation in renal TECs
We examined the effect of NSC828779 on rIL-36α-induced NLRP3 inflammasome activation in macrophages
Summary
Renal tubulointerstitial lesions (TILs), characterized by inflammation and fibrosis of the kidneys, are key pathological findings underlying progression to end-stage renal disease [1,2]. IL-36α (IL-1F6), a proinflammatory cytokine, is essential for innate and adaptive immunity [3] In psoriasis, it triggers early activation of STAT3, NF-κB, and MAPKs in keratinocytes [4]. We found that activation of IL-36 signaling is implicated in renal inflammation and fibrosis in a mouse unilateral ureteral obstruction (UUO) model. Other studies confirm that pathogenesis of renal TILs in the UUO model involves NLRP3 inflammasome activation [6,7,8,9]. Our recent study confirms that STAT3 signaling and NLRP3 inflammasome work together as a major pathogenic pathway underlying TILs in UUO [17]. We tested the hypothesis that NSC828779 has therapeutic effects on renal inflammation and fibrosis using a mouse model of UUO and relevant cell models, and further investigated the mode of action of this small molecule
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
