Abstract
Renal fibrosis is controlled by profibrotic and antifibrotic forces. Exploring anti-fibrosis factors and mechanisms is an attractive strategy to prevent organ failure. Here we identified the JNK-associated leucine zipper protein (JLP) as a potential endogenous antifibrotic factor. JLP, predominantly expressed in renal tubular epithelial cells (TECs) in normal human or mouse kidneys, was downregulated in fibrotic kidneys. Jlp deficiency resulted in more severe renal fibrosis in unilateral ureteral obstruction (UUO) mice, while renal fibrosis resistance was observed in TECs-specific transgenic Jlp mice. JLP executes its protective role in renal fibrosis via negatively regulating TGF-β1 expression and autophagy, and the profibrotic effects of ECM production, epithelial-to-mesenchymal transition (EMT), apoptosis and cell cycle arrest in TECs. We further found that TGF-β1 and FGF-2 could negatively regulate the expression of JLP. Our study suggests that JLP plays a central role in renal fibrosis via its negative crosstalk with the profibrotic factor, TGF-β1.
Highlights
Renal fibrosis is controlled by profibrotic and antifibrotic forces
We found that ureteral obstruction (UUO) led to increase the number of injured tubules and percentage of interstitial fibrosis in kidneys from Jlp−/− mice compared to kidneys from Jlp+/+ mice as examined by hematoxylin-eosin (HE) staining and masson trichrome staining (MTS) (Fig. 1a)
TGF-β1 is the critical driver in renal fibrosis for its formidable and comprehensive capability to promote extra cellular matrix (ECM) production, epithelial-to-mesenchymal transition (EMT), apoptosis and cell cycle on TECs66, which has been suggested as a promising therapeutic target
Summary
Renal fibrosis is controlled by profibrotic and antifibrotic forces. Exploring anti-fibrosis factors and mechanisms is an attractive strategy to prevent organ failure. JLP is positively expressed in various human cancer or malignant diseases to increase cancer cells abilities of survival, proliferation, migration, and invasion[36,37,38,39,40,41,42,43,44,45], and its overexpression is of great interest for diagnosis and prognosis[39,41,46,47,48,49,50,51,52,53,54,55] These studies herald the emerging of JLP as a promising therapy target and a potential biomarker in cancer disease. This phenomenon led us speculate that JLP possess the capacities of tumorigenicity promotion, as well as fibrosis resistance, and its upregulation or loss contributes to the distinct different diseases of tumor or fibrosis
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