2. Academic Validation
  3. Renal tubular S100A7a impairs fatty acid oxidation and exacerbates renal fibrosis via both intracellular and extracellular pathway

Renal tubular S100A7a impairs fatty acid oxidation and exacerbates renal fibrosis via both intracellular and extracellular pathway

  • Biochim Biophys Acta Mol Basis Dis. 2025 Mar;1871(3):167656. doi: 10.1016/j.bbadis.2025.167656.
Pengxiao Sun 1,  Qingzhou Chen 1,  Xiaomei Chen 1,  Jiaxin Zhou 1,  Tantan Long 1,  Yuanyuan Ma 1,  Miaomiao Zhou 1,  Zheng Hu 1,  Jianwei Tian 1,  Fengxin Zhu 1,  Zhenhua Yang 2,  Liling Xie 1,  Qiaoyuan Wu 3,  Jing Nie 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
  • 2 Department of Nephrology, The First Affiliated Hospital, Guangxi Medical University, Nanning 530021, China.
  • 3 Department of Nephrology, The First Affiliated Hospital, Guangxi Medical University, Nanning 530021, China. Electronic address: 236071507@qq.com.
  • 4 State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Biobank of Peking University First Hospital, Peking University First Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University Health Science Center, Peking University, Beijing 100034, China. Electronic address: niejing@smu.edu.cn.
PMID: 39778778 DOI: 10.1016/j.bbadis.2025.167656
Abstract

A couple of S100 family proteins (S100s) have been reported to exert pro-inflammatory functions in the progression of renal fibrosis. Unlike some S100s which are expressed by both epithelial and stromal inflammatory cells, S100A7 is restricted expressed in epithelium. Persistent S100A7 expression occurs in some invasive carcinomas and is associated with poor prognostic factors. Whereas, whether it is implicated in renal tubular epithelial cell injury and kidney disease remains unexplored. In this study, we demonstrate that S100A7 is highly upregulated in tubular cells of both mouse renal fibrotic lesions and kidney biopsies from patients with chronic kidney disease (CKD). The level of renal S100A7 was associated with both the decline of renal function and the progression of renal fibrosis in CKD patients. Overexpressing S100A7a impaired fatty acid oxidation (FAO) and promoted lipid peroxidation in proximal tubular cells (PTCs). Mechanistically, S100A7a interacts with β-catenin, thereby preventing its ubiquitination and degradation by the β-TrCP-SCF complex, and in turn activated β-catenin signaling, downregulated the expression of PGC-1α. Additionally, S100A7a exacerbated lipid peroxidation via RAGE-p-ERK-NOX2 pathway. Specific deletion of S100a7a in tubular cells enhanced FAO and reduced lipid peroxidation, resulting in improved renal function and alleviation of renal fibrosis induced by unilateral ureteral obstruction and unilateral ischemia-reperfusion injury. Collectively, we delineate a previously unrecognized function of S100A7a in the progression of renal fibrosis.

Keywords

Chronic kidney disease; Fatty acid oxidation; Renal fibrosis; S100A7a; Tubular epithelial cells; β-Catenin signaling.

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