NSC828779 Alleviates Renal Tubulointerstitial Lesions Involving Interleukin-36 Signaling in Mice
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
Affiliations
Shin-Ruen Yang
Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan
Szu-Chun Hung
Division of Nephrology, Taipei Tzu Chi Hospital, Taipei 23142, Taiwan
Lichieh Julie Chu
Molecular Medicine Research Center, Chang Gung University, Taoyuan 33302, Taiwan
Kuo-Feng Hua
Department of Biotechnology and Animal Science, National Ilan University, Ilan 260007, Taiwan
Chyou-Wei Wei
Department of Nutrition, Master Program of Biomedical Nutrition, Hungkuang University, Taichung 433304, Taiwan
I-Lin Tsai
Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
Chih-Chin Kao
Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 11031, Taiwan
Chih-Chien Sung
Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan
Pauling Chu
Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan
Chung-Yao Wu
Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan
Ann Chen
Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan
Alexander T. H. Wu
The PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
Feng-Cheng Liu
Division of Rheumatology/Immunology and Allergy, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan
Hsu-Shan Huang
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11301, Taiwan
Shuk-Man Ka
Graduate Institute of Aerospace and Undersea Medicine, Department of Medicine, National Defense Medical Center, Taipei 11490, Taiwan
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.
