The antihelmenthic phosphate niclosamide impedes renal fibrosis by inhibiting homeodomain-interacting protein kinase 2 expression.
Renal fibrosis is the final common pathway of all varieties of progressive chronic kidney disease. However, there are no effective therapies to prevent or slow the progression of renal fibrosis. Niclosamide is a US Food and Drug Administration-approved oral antihelminthic drug used for treating most tapeworm infections. Here, we demonstrated that phosphate niclosamide, the water-soluble form of niclosamide, significantly reduced proteinuria, glomerulosclrotic lesions, and interstitial fibrosis in a murine model of adriamycin nephropathy. In addition, phosphate niclosamide significantly ameliorated established renal interstitial fibrosis a murine model of unilateral ureteral obstruction. Mechanistically, phosphate niclosamide directly inhibited TGF-β-induced expression of homeodomain-interacting protein kinase 2 (HIPK2) by interfering with the binding of Smad3 to the promoter of the HIPK2 gene, and subsequently mitigated the activation of its downstream signaling pathways including Smad, Notch, NF-κB and Wnt/β-catenin pathway both in vitro and in vivo. Thus, phosphate niclosamide mitigates renal fibrosis at least partially by inhibiting HIPK2 expression. Hence, phosphate niclosamide might be a potential therapeutic agent for renal fibrosis.
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Laboratory of Organ Failure Research, Ministry of Education, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Xiaoyan
X
Chang
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Laboratory of Organ Failure Research, Ministry of Education, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Xin
X
Zhen
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Laboratory of Organ Failure Research, Ministry of Education, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Jixing
J
Liu
School of Pharmacy, Jinan University, Guangzhou, China.
Xiaomei
X
Ren
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Laboratory of Organ Failure Research, Ministry of Education, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Zheng
Z
Hu
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Laboratory of Organ Failure Research, Ministry of Education, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Zhanmei
Z
Zhou
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Laboratory of Organ Failure Research, Ministry of Education, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Fengxin
F
Zhu
School of Pharmacy, Jinan University, Guangzhou, China.
Ke
K
Ding
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Laboratory of Organ Failure Research, Ministry of Education, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China. Electronic address: niejing@smu.edu.cn.
Jing
J
Nie
D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology* / Q000627:therapeutic use; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000633:toxicity; D005355:Fibrosis; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D009534:Niclosamide / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011507:Proteinuria / Q000188:drug therapy / Q000652:urine; D051381:Rats; D051880:Receptors, Notch / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000652:urine; D051785:Smad Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects
D000871:Anthelmintics; D002352:Carrier Proteins; D016328:NF-kappa B; D051880:Receptors, Notch; D051785:Smad Proteins; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D004317:Doxorubicin; D009534:Niclosamide; C492003:Hipk2 protein, mouse; D017346:Protein Serine-Threonine Kinases
HIPK2; Notch; Smad; Wnt/β-catenin; phosphate niclosamide; renal fibrosis