NSC828779 Alleviates Renal Tubulointerstitial Lesions Involving Interleukin-36 Signaling in Mice

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 i...

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Autores principales:	Shin-Ruen Yang, Szu-Chun Hung, Lichieh Julie Chu, Kuo-Feng Hua, Chyou-Wei Wei, I-Lin Tsai, Chih-Chin Kao, Chih-Chien Sung, Pauling Chu, Chung-Yao Wu, Ann Chen, Alexander T. H. Wu, Feng-Cheng Liu, Hsu-Shan Huang, Shuk-Man Ka
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	salicylanilide derivative tubulointerstitial lesions IL-36α mechanically induced constant pressure IL-36α/NLRP3 inflammasome Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/a2306ac572bc4bf5b23db0435511be33
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spelling	oai:doaj.org-article:a2306ac572bc4bf5b23db0435511be332021-11-25T17:10:59ZNSC828779 Alleviates Renal Tubulointerstitial Lesions Involving Interleukin-36 Signaling in Mice10.3390/cells101130602073-4409https://doaj.org/article/a2306ac572bc4bf5b23db0435511be332021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/3060https://doaj.org/toc/2073-4409Renal 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 IC<sub>50</sub>, 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.Shin-Ruen YangSzu-Chun HungLichieh Julie ChuKuo-Feng HuaChyou-Wei WeiI-Lin TsaiChih-Chin KaoChih-Chien SungPauling ChuChung-Yao WuAnn ChenAlexander T. H. WuFeng-Cheng LiuHsu-Shan HuangShuk-Man KaMDPI AGarticlesalicylanilide derivativetubulointerstitial lesionsIL-36αmechanically induced constant pressureIL-36α/NLRP3 inflammasomeBiology (General)QH301-705.5ENCells, Vol 10, Iss 3060, p 3060 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	salicylanilide derivative tubulointerstitial lesions IL-36α mechanically induced constant pressure IL-36α/NLRP3 inflammasome Biology (General) QH301-705.5
spellingShingle	salicylanilide derivative tubulointerstitial lesions IL-36α mechanically induced constant pressure IL-36α/NLRP3 inflammasome Biology (General) QH301-705.5 Shin-Ruen Yang Szu-Chun Hung Lichieh Julie Chu Kuo-Feng Hua Chyou-Wei Wei I-Lin Tsai Chih-Chin Kao Chih-Chien Sung Pauling Chu Chung-Yao Wu Ann Chen Alexander T. H. Wu Feng-Cheng Liu Hsu-Shan Huang Shuk-Man Ka NSC828779 Alleviates Renal Tubulointerstitial Lesions Involving Interleukin-36 Signaling in Mice
description	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 IC<sub>50</sub>, 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.
format	article
author	Shin-Ruen Yang Szu-Chun Hung Lichieh Julie Chu Kuo-Feng Hua Chyou-Wei Wei I-Lin Tsai Chih-Chin Kao Chih-Chien Sung Pauling Chu Chung-Yao Wu Ann Chen Alexander T. H. Wu Feng-Cheng Liu Hsu-Shan Huang Shuk-Man Ka
author_facet	Shin-Ruen Yang Szu-Chun Hung Lichieh Julie Chu Kuo-Feng Hua Chyou-Wei Wei I-Lin Tsai Chih-Chin Kao Chih-Chien Sung Pauling Chu Chung-Yao Wu Ann Chen Alexander T. H. Wu Feng-Cheng Liu Hsu-Shan Huang Shuk-Man Ka
author_sort	Shin-Ruen Yang
title	NSC828779 Alleviates Renal Tubulointerstitial Lesions Involving Interleukin-36 Signaling in Mice
title_short	NSC828779 Alleviates Renal Tubulointerstitial Lesions Involving Interleukin-36 Signaling in Mice
title_full	NSC828779 Alleviates Renal Tubulointerstitial Lesions Involving Interleukin-36 Signaling in Mice
title_fullStr	NSC828779 Alleviates Renal Tubulointerstitial Lesions Involving Interleukin-36 Signaling in Mice
title_full_unstemmed	NSC828779 Alleviates Renal Tubulointerstitial Lesions Involving Interleukin-36 Signaling in Mice
title_sort	nsc828779 alleviates renal tubulointerstitial lesions involving interleukin-36 signaling in mice
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/a2306ac572bc4bf5b23db0435511be33
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NSC828779 Alleviates Renal Tubulointerstitial Lesions Involving Interleukin-36 Signaling in Mice

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