A dual role of AcSDKP in chronic kidney disease: Targeting pericyte-driven fibrosis and vascular repair via VEGF/FGFR1 while eliciting a compensatory FGFR1 upregulation in apoptotic tubular cells
6 affiliations
- 1Kidney Pathology and Immunology Laboratory, Pediatric Clinical Research Institute of Soochow University, Pediatric Clinical Medical College of Soochow University, Children’s Hospital of Soochow University, Soochow, China
- 2Pediatric Department, Suzhou Municipal Hospital & Department of Nephrology and Immunology, Children’s Hospital of Soochow University, Soochow, China
- 3Department of Nephrology and Immunology, Children’s Hospital of Soochow University, Soochow, China
- 4Electronic Information School of Wuhan University, Wuhan, China
- 5Pediatric Clinical Research Institute of Soochow University, Pediatric Clinical Medical College of Soochow University, Children’s Hospital of Soochow University, Soochow, China
- 6Pediatric Clinical Research Institute of Soochow University, Pediatric Clinical Medical College of Soochow University, Department of Nephrology and Immunology, Children’s Hospital of Soochow University, Soochow, China
Abstract
Background: Renal interstitial fibrosis and peritubular capillary (PTC) rarefaction drive the progression of chronic kidney disease (CKD). While N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is an endogenous anti-fibrotic peptide, its specific effects on pericyte-endothelial crosstalk and tubular epithelial survival remain controversial. Methods: We employed a self-controlled unilateral aristolochic acid (AA)-induced CKD mouse model to evaluate the time-sensitive efficacy of AcSDKP. In vitro, primary murine pericytes, human tubular epithelial cells (HK-2), and endothelial cells were utilized. Functional mechanisms were dissected using VEGF ELISA, RNA-sequencing, and targeted FGFR1 siRNA knockdown. Results: In vitro, AcSDKP potently suppressed TGF-β1-induced pericyte-to-myofibroblast transition (PMT) and robustly restored pericyte-derived VEGF secretion, thereby rescuing endothelial tubulogenesis. In vivo, early AcSDKP intervention (Week 3) significantly mitigated fibrosis, preserved capillary integrity, and improved systemic renal function (BUN/SCr), whereas late intervention (Week 4) was less effective. Transcriptomics identified the VEGF/FGFR1 axis as a primary target of AcSDKP. However, in AA-injured HK-2 cells, AcSDKP paradoxically exacerbated apoptosis despite upregulating FGFR1. Subsequent siRNA knockdown revealed that silencing FGFR1 drastically worsened apoptosis, proving that endogenous FGFR1 upregulation is a compensatory survival response. AcSDKP’s epithelial toxicity is fundamentally FGFR1-independent, driven instead by its concurrent inhibition of the Akt survival pathway. Conclusion: AcSDKP exerts a compartment-specific dual role in CKD. It is a potent vascular protector that halts PMT and promotes VEGF-driven endothelial repair, but acts as a pro-apoptotic stressor in severely damaged tubules. Its clinical translation necessitates early-stage intervention and optimized delivery strategies to maximize vascular benefits while mitigating epithelial toxicity.
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BibTeX
@article{zhu2026dual,
title = {{A dual role of AcSDKP in chronic kidney disease: Targeting pericyte-driven fibrosis and vascular repair via VEGF/FGFR1 while eliciting a compensatory FGFR1 upregulation in apoptotic tubular cells}},
author = {Shiyi Zhu and Lingli Shi and Linlin Huang and Ningxun Cui and Ruyue Chen and Lu Jiang and Annan Zhang and Yunyun Xu and Xiaozhong Li},
journal = {PLOS One},
year = {2026},
month = sep,
doi = {10.1371/journal.pone.0355409},
url = {https://doi.org/10.1371/journal.pone.0355409},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A dual role of AcSDKP in chronic kidney disease: Targeting pericyte-driven fibrosis and vascular repair via VEGF/FGFR1 while eliciting a compensatory FGFR1 upregulation in apoptotic tubular cells
AU - Shiyi Zhu
AU - Lingli Shi
AU - Linlin Huang
AU - Ningxun Cui
AU - Ruyue Chen
AU - Lu Jiang
AU - Annan Zhang
AU - Yunyun Xu
AU - Xiaozhong Li
PY - 2026
DA - 2026/09/11
JO - PLOS One
DO - 10.1371/journal.pone.0355409
UR - https://doi.org/10.1371/journal.pone.0355409
AB - Background: Renal interstitial fibrosis and peritubular capillary (PTC) rarefaction drive the progression of chronic kidney disease (CKD). While N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is an endogenous anti-fibrotic peptide, its specific effects on pericyte-endothelial crosstalk and tubular epithelial survival remain controversial. Methods: We employed a self-controlled unilateral aristolochic acid (AA)-induced CKD mouse model to evaluate the time-sensitive efficacy of AcSDKP. In vitro, primary murine pericytes, human tubular epithelial cells (HK-2), and endothelial cells were utilized. Functional mechanisms were dissected using VEGF ELISA, RNA-sequencing, and targeted FGFR1 siRNA knockdown. Results: In vitro, AcSDKP potently suppressed TGF-β1-induced pericyte-to-myofibroblast transition (PMT) and robustly restored pericyte-derived VEGF secretion, thereby rescuing endothelial tubulogenesis. In vivo, early AcSDKP intervention (Week 3) significantly mitigated fibrosis, preserved capillary integrity, and improved systemic renal function (BUN/SCr), whereas late intervention (Week 4) was less effective. Transcriptomics identified the VEGF/FGFR1 axis as a primary target of AcSDKP. However, in AA-injured HK-2 cells, AcSDKP paradoxically exacerbated apoptosis despite upregulating FGFR1. Subsequent siRNA knockdown revealed that silencing FGFR1 drastically worsened apoptosis, proving that endogenous FGFR1 upregulation is a compensatory survival response. AcSDKP’s epithelial toxicity is fundamentally FGFR1-independent, driven instead by its concurrent inhibition of the Akt survival pathway. Conclusion: AcSDKP exerts a compartment-specific dual role in CKD. It is a potent vascular protector that halts PMT and promotes VEGF-driven endothelial repair, but acts as a pro-apoptotic stressor in severely damaged tubules. Its clinical translation necessitates early-stage intervention and optimized delivery strategies to maximize vascular benefits while mitigating epithelial toxicity.
SN - 1932-6203
ER -