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Front Pharmacol. 2019 Aug 9;10:880. doi: 10.3389/fphar.2019.00880. eCollection 2019.

Combined Blockade of Smad3 and JNK Pathways Ameliorates Progressive Fibrosis in Folic Acid Nephropathy.

Jiang M1,2, Fan J3,4, Qu X2, Li S5,6, Nilsson SK5,6, Sun YBY2, Chen Y7, Yu D7, Liu D8, Liu BC8, Tang M9, Chen W3,4, Ren Y10, Nikolic-Paterson DJ11, Jiang X1, Li J2,4,12, Yu X4,12,13.

Author information

1
Department of Pediatrics, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
2
Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.
3
Department of Nephrology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
4
Key Laboratory of Nephrology, National Health Commission and Guangdong Province, Guangzhou, China.
5
Biomedical Manufacturing Commonwealth Scientific and Industrial Research Organisation (CSIRO), Melbourne, VIC, Australia.
6
Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia.
7
Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia.
8
Institute of Nephrology, Zhong Da Hospital, Southeast University, Nanjing, China.
9
Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, China.
10
Florida State University College of Medicine, Tallahassee, FL, United States.
11
Department of Nephrology, Monash Health and Monash University Department of Medicine, Clayton, VIC, Australia.
12
The Second Clinical College and Shunde Women and Children Hospital, Guangdong Medical University, Shunde, China.
13
Guangdong Academy of Medical Science, Guangdong Provincial People's Hospital, Guangzhou, China.

Abstract

Acute kidney injury leading to chronic kidney disease through tubulointerstitial fibrosis is a major challenge in nephropathy. Several signaling 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 c-Jun N-terminal kinase (JNK) signaling 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-activations of Smad3 and JNK signaling 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 FA 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 signaling 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 signaling 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 signaling 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:

JNK1/2; PGC-1α; Smad3; mitochondrial dysfunction; tubulointerstitial fibrosis

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