Inhibition of apoptosis signal-regulating kinase 1 mitigates the pathogenesis of human immunodeficiency virus-associated nephropathy

作者全名："Chen, Anqun; Xu, Jin; Lai, Han; D'Agati, Vivette D.; Guan, Tian-Jun; Badal, Shawn; Liles, John; He, John C.; Lee, Kyung"

作者地址："[Chen, Anqun; Xu, Jin; Lai, Han; He, John C.; Lee, Kyung] Icahn Sch Med Mt Sinai, Dept Med, Div Nephrol, New York, NY 10029 USA; [Chen, Anqun; Guan, Tian-Jun] Xiamen Univ, Zhongshan Hosp, Div Nephrol, Xiamen, Peoples R China; [Lai, Han] Chongqing Med Univ, Dept Nephrol, Affiliated Hosp 1, Chongqing, Peoples R China; [D'Agati, Vivette D.] Columbia Med Sch, Dept Pathol, New York, NY USA; [Badal, Shawn; Liles, John] Gilead Sci Inc, 353 Lakeside Dr, Foster City, CA 94404 USA; [He, John C.] James J Peters VA Med Ctr, Kidney Ctr, Bronx, NY 10468 USA"

通信作者："He, JC; Lee, K (corresponding author), Icahn Sch Med Mt Sinai, Dept Med, Div Nephrol, New York, NY 10029 USA.; He, JC (corresponding author), James J Peters VA Med Ctr, Kidney Ctr, Bronx, NY 10468 USA."

来源：NEPHROLOGY DIALYSIS TRANSPLANTATION

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000646227900010

JCR分区：Q1

影响因子：6.1

年份：2021

卷号：36

期号：3

开始页：430

结束页：441

文献类型：Article

关键词：albuminuria; ASK1; fibrosis; glomerulosclerosis; HIVAN; inflammation; podocyte

摘要："Background. Chronic kidney disease (CKD) is a common cause of morbidity and mortality in human immunodeficiency virus (HIV)-positive individuals. Among the HIV-related kidney diseases, HIV-associated nephropathy (HIVAN) is a rapidly progressive renal disease characterized by collapsing focal glomerulosclerosis (GS), microcystic tubular dilation, interstitial inflammation and fibrosis. Although the incidence of end-stage renal disease due to HIVAN has dramatically decreased with the widespread use of antiretroviral therapy, the prevalence of CKD continues to increase in HIV-positive individuals. Recent studies have highlighted the role of apoptosis signal-regulating kinase 1 (ASK1) in driving kidney disease progression through the activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase and selective ASK-1 inhibitor GS-444217 was recently shown to reduce kidney injury and disease progression in various experimental models. Therefore we examined the efficacy of ASK1 antagonism by GS-444217 in the attenuation of HIVAN in Tg26 mice. Methods. GS-444217-supplemented rodent chow was administered in Tg26 mice at 4weeks of age when mild GS and proteinuria were already established. After 6weeks of treatment, the kidney function assessment and histological analyses were performed and compared between age- and gender-matched control Tg26 and GS-444217-treated Tg26 mice. Results. GS-444217 attenuated the development of GS, podocyte loss, tubular injury, interstitial inflammation and renal fibrosis in Tg26 mice. These improvements were accompanied by a marked reduction in albuminuria and improved renal function. Taken together, GS-4442217 attenuated the full spectrum of HIVAN pathology in Tg26 mice. Conclusions. ASK1 signaling cascade is central to the development of HIVAN in Tg26 mice. Our results suggest that the select inhibition of ASK1 could be a potential adjunctive therapy for the treatment of HIVAN."

基金机构："Gilead Sciences (Foster City, CA, USA)Gilead Sciences; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81800637]; Natural Science Foundation of Fujian ProvinceNatural Science Foundation of Fujian Province [2019J01560]; Xiamen Science and Technology Project [3502Z20194014]; Veterans Affairs Merit AwardUS Department of Veterans Affairs; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [R01DK078897, R01DK088541, P01DK56492]; NIDDKUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [R01DK117913]"

基金资助正文："Funding for the project was provided by Gilead Sciences (Foster City, CA, USA). A.C. is supported by the National Natural Science Foundation of China(81800637), Natural Science Foundation of Fujian Province (2019J01560) and the Xiamen Science and Technology Project (grant 3502Z20194014). J.C.H. is supported by a Veterans Affairs Merit Award and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; R01DK078897, R01DK088541 and P01DK56492). K.L. is supported by the NIDDK (R01DK117913)."