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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2019.00880

Combined blockade of Smad3 and JNK pathways ameliorates progressive fibrosis in folic acid nephropathy

 Mengjie Jiang1, Jinjin Fan2, Xinli Qu3, Songhui Li4, Susan K. Nilsson4,  Yu Bo Y. Sun5, Yaping Chen6,  Di Yu6, Dan Liu7,  Bi-Cheng Liu7,  Mingliang Tang8, Wei Chen2, Yi Ren9,  David J. Nikolic-Paterson10, Xiaoyun Jiang1, 11*,  Jinhua Li12* and Xueqing Yu13*
  • 1Department of Pediatrics, First Affiliated Hospital of Sun Yat-sen University, China
  • 2Department of Nephrology, First Affiliated Hospital, Sun Yat‐Sen University, China
  • 3Monash University, Australia
  • 4Biomedical Manufacturing, Commonwealth Scientific and Industrial Research Organisation, Australia
  • 5Department of Anatomy and Developmental Biology, Monash University, Australia
  • 6Biomedicine Discovery Institute, Monash University, Australia
  • 7Institute of Nephrology, Zhongda Hospital, Southeast University, China
  • 8Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, China
  • 9College of Medicine, Florida State University, United States
  • 10Department of Nephrology, Monash Health, Australia
  • 11Department of Pediatrics, First Affiliated Hospital of Sun Yat-sen University, China
  • 12Department of Anatomy and Developmental Biology, Monash University, Australia
  • 13Guangdong Academy of Medical Sciences, China

Acute kidney injury leading to chronic kidney disease through tubulointerstitial fibrosis is a major challenge in nephropathy. Several signalling pathways promote interstitial fibrosis; however, effective suppression of fibrosis may require blockade of more than one pathway. This study investigated whether blockade of Smad3 and JNK signalling gives added suppression of interstitial fibrosis in folic acid nephropathy. A single high dose of folic acid (FA) causes acute tubular damage in C57BL/6J mice followed by interstitial fibrosis and chronic renal impairment. Co-activation of Smad3 and JNK signalling occur in both tubular epithelial cells and myofibroblasts in areas of tubulointerstitial damage and fibrosis in both murine FA-induced nephropathy and human IgA nephropathy. Groups of mice were treated with a Smad3 inhibitor (SIS3), a JNK inhibitor (SP600125), or a combination from day 6 after folic acid administration until being killed on day 28. Each drug efficiently inhibited its specific target (Smad3 phosphorylation or c–Jun phosphorylation) without affecting the other pathway. Given alone, each drug partially reduced renal fibrosis, whereas the combination therapy gave an additive and profound protection from renal fibrosis and improved renal function. Inhibition of Smad3 and/or JNK signalling activities prevented down-regulation of PGC-1α in tubular epithelial cells and up-regulation of PGC-1α in myofibroblasts during FA-induced renal fibrosis and inflammation. The expression of PGC-1α was upregulated in Smad3-/- NRK52E cells while downregulated in Smad3-/- NRK49F cells, suggesting that Smad3 signalling may regulate expression of PGC-1α in renal tubular epithelial cells and fibroblasts in distinct fashion. In vivo and cell culture studies also indicate that Smad3 and JNK signalling cooperate to cause mitochondrial dysfunction and cell damage in tubular epithelial cells via direct actions on the transcription of PGC-1α. These pathways also act cooperatively to promote renal fibroblast proliferation in tempo-spatial fashion. In conclusion, we have identified a potential combination therapy for progressive renal fibrosis which operates, in part, through modifying mitochondrial function.

Keywords: Tubulointerstitial fibrosis, Smad3, JNK, PGC-1 alpha, mitochondrial dysfunction

Received: 02 May 2019; Accepted: 10 Jul 2019.

Edited by:

Xueying Zhao, Morehouse School of Medicine, United States

Reviewed by:

Isha Sharma, Feinberg School of Medicine, Northwestern University, United States
Zhengrong Guan, University of Alabama at Birmingham, United States  

Copyright: © 2019 Jiang, Fan, Qu, Li, Nilsson, Sun, Chen, Yu, Liu, Liu, Tang, Chen, Ren, Nikolic-Paterson, Jiang, Li and Yu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Prof. Xiaoyun Jiang, Department of Pediatrics, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China, xyjiang-3208@163.com
PhD. Jinhua Li, Monash University, Department of Anatomy and Developmental Biology, Melbourne, Australia, jinhua.li@monash.edu
Mx. Xueqing Yu, Guangdong Academy of Medical Sciences, Guangzhou, China, yuxq@mail.sysu.edu.cn