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EVA1A responds to endoplasmic reticulum stress to regulate renal fibrosis by promoting TGF-β signaling pathway
Qiongdan Gao1, Zhenkun Wang2, Yuting Fu2
1Division of Nephrology, Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease; State Key Laboratory of Multi-organ Injury Prevention and Treatment; Guangdong Provincial Institute of Nephrology; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou 510515, China.
Introduction:
Renal fibrosis is a common pathological hallmark of chronic kidney disease (CKD), and ultimately leads to end-stage renal disease. ER-stress and TGF-β signaling pathway activation play critical roles in renal fibrosis, but the precise mechanisms underlying the intricate interplay between ER-stress and TGF-β signaling pathway remain ambiguous. Our previous study has demonstrated that EVA1A responds to ER-stress to regulate hematopoietic stem cell regeneration; However, the function of EVA1A in renal fibrosis remains unexplored.
Objectives:
To elucidate the role of EVA1A in TGF-β signaling regulation and renal fibrosis.
Methods:
We characterized EVA1A expression changes in chronic kidney disease through single-cell RNA-seq data analysis, immunohistochemical staining and Western blot analysis. Eva1a conditional knockout mouse subjected to unilateral-ischemia-reperfusion-injury (UIRI) and unilateral-ureteral-obstruction (UUO), two well-established and widely used fibrosis-related CKD mouse models, were used to investigate the role of EVA1A in renal fibrosis. Subsequently, we characterized the interaction of EVA1A and TGF-β receptor type Ⅱ (TGFBR2) by co-immunoprecipitation and bimolecular-fluorescence-complementation (BiFC) assays to clarify the regulatory mechanism of EVA1A in TGF-β signaling.
Results:
We found that EVA1A was significantly upregulated in fibrotic kidneys from CKD patients and mice with UUO or UIRI treatment. Deletion of Eva1a significantly attenuated kidney fibrosis and damage in mice with UUO or UIRI treatment. Overexpression of EVA1A enhanced fibrosis levels in mice with UUO treatment and upregulated the expression of fibrosis-related proteins in cultured renal epithelial cells. Mechanistically, we found that ER stress upregulates EVA1A expression via CHOP in CKD mouse model. Subsequently, EVA1A interacted with BIP to stabilize and facilitate the secretion of TGFBR2 from ER to plasma membrane, thereby promoting TGF-β signaling activation and renal fibrosis.
Conclusion:
During the progression of CKD, EVA1A serves as a sensor for ER stress and regulates renal fibrosis by promoting TGF-β signaling pathway activity.
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