RARRES1 Promotes Tubular Fibrosis via the KHDRBS1/Src/p-STAT3 Axis
Journal of the American Society of Nephrology, 2026
Ye L., Jiang Z., Wu Y., Zeng Y., Chen X., Feng B., Yin L., Gao Y., Xu W., Yan S., Li Y., Wu J., Li Q., Chen A.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Nephrology | Pathophysiology | Plasma |  Olink Explore 3072/384 |
Abstract
Background:
Kidney fibrosis is a hallmark of chronic kidney disease (CKD), yet its underlying mechanisms remain incompletely understood. Retinoic acid receptor responder protein 1 (RARRES1) is largely restricted to podocytes in healthy kidneys but was upregulated within the tubulointerstitium in CKD. However, its functional contribution to kidney fibrosis remains unclear.
Methods:
To assess the link between tubulointerstitial RARRES1 expression, estimated glomerular filtration rate (eGFR), and fibrosis severity in CKD patients, we analyzed multiple clinical datasets. RARRES1 upregulation in proximal tubular epithelial cells was confirmed in human CKD samples by immunofluorescence and RNAscope assays. Kidney fibrosis was evaluated in proximal tubule-specific Rarres1 knockout mice and RARRES1-overexpressing mice following CKD induction, including unilateral ureteral obstruction (UUO) and folic acid-induced nephropathy. Mechanistically, mass spectrometry and co-immunoprecipitation, combined with truncation mutants, uncovered interactions among soluble RARRES1, KHDRBS1, Src kinase, and phosphorylated STAT3. Pharmacological blockade of STAT3 or Src kinase were used to evaluate the reversal of RARRES1-induced fibrotic phenotype.
Results:
Multiple datasets revealed that tubulointerstitial RARRES1 expression correlated with decreased eGFR and increased fibrosis severity in CKD patients. Immunofluorescence and RNAscope confirmed RARRES1 upregulation specifically in proximal tubular epithelial cells in CKD. Proximal tubule-specific knockout of Rarres1 significantly attenuated kidney fibrosis in two independent CKD models. Conversely, RARRES1-overexpressing mice showed aggravated kidney fibrosis compared to controls in the UUO model. Soluble RARRES1 was identified as the key pathogenic form, with its plasma levels correlating with declining kidney function in CKD patients. Mechanistically, soluble RARRES1 bound KHDRBS1, recruited Src kinase, and induced STAT3 phosphorylation at Tyr705, leading to upregulation of pro-fibrotic factors. Inhibition of STAT3 or Src kinase partially reversed the fibrotic phenotype induced by RARRES1 overexpression.
Conclusions:
Our findings demonstrated that RARRES1 played an important role in regulating kidney fibrosis through the KHDRBS1-Src-p-STAT3 signaling axis.