2. Academic Validation
  3. Pharmacologic deprivation of serum inorganic phosphate ameliorates renal fibrosis via the modulation of systemic inflammation

Pharmacologic deprivation of serum inorganic phosphate ameliorates renal fibrosis via the modulation of systemic inflammation

  • Eur J Pharmacol. 2026 Jan 12:1011:178430. doi: 10.1016/j.ejphar.2025.178430.
Mei-Diao Kang 1,  Qing Deng 2,  Yuan-Yuan Zhang 1,  Zi-Qiang Liao 3,  Ze-Ning Chen 3,  Qing-Rong Liang 3,  Rong-Guang Luo 4,  Zhi-Qiang Deng 5,  Jin-Lei Lv 6,  Qun Tang 7
Affiliations

Affiliations

  • 1 The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Pharmacology, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China; Key Laboratory of New Drug Transformation and Evaluation of Jiangxi Province, Nanchang, 330006, China.
  • 2 Institute of Molecular Immunology for Kidney Disease, Department of Nephrology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.
  • 3 The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Pharmacology, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.
  • 4 Department of Medical Imaging and Interventional Radiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.
  • 5 Department of Oncology, The First People's Hospital of Fuzhou, Fuzhou, China.
  • 6 Institute of Molecular Immunology for Kidney Disease, Department of Nephrology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China. Electronic address: [email protected].
  • 7 The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Pharmacology, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China; Key Laboratory of New Drug Transformation and Evaluation of Jiangxi Province, Nanchang, 330006, China. Electronic address: [email protected].
PMID: 41344535 DOI: 10.1016/j.ejphar.2025.178430
Abstract

Renal fibrosis is a common feature of chronic kidney disease (CKD) and is characterized by interstitial fibrotic tissue deposition, impaired renal function, and interstitial inflammation. To date, there are no clinically effective therapeutic agents specifically approved for the treatment of renal fibrosis. Sevelamer, as a phosphate binder, was approved to treat hyperphosphatemia and was recently shown to have antifibrotic effects in preclinical studies. In this study, we established a folic acid (FA)-induced renal interstitial fibrosis mouse model and an in vitro model using human kidney-2 (HK-2) cells to evaluate the therapeutic effects and mechanisms of sevelamer in renal fibrosis. Our results revealed that sevelamer reduced serum phosphate levels in fibrotic mice and improved renal function by restoring serum creatinine (Scr), blood urea nitrogen (BUN), and uric acid (UA) levels. Sevelamer significantly alleviated tubular injury, reduced extracellular matrix (ECM) accumulation, decreased the expression of inflammatory cytokines (IL-1β, IL-6, and TNF-α) in the serum, and mitigated renal inflammation. In vitro, sevelamer-induced phosphate deprivation inhibited HK-2 cell migration and epithelial‒mesenchymal transition (EMT), reducing the expression of fibrosis-associated proteins. Mechanistic studies revealed that low-phosphate stress induced by sevelamer suppressed the phosphorylation of IκBα and NF-κB-p65, inhibiting nuclear factor kappa B (NF-κB) signaling both in vivo and in vitro. As a result, sevelamer-mediated low-phosphate stress improved renal function, reduced ECM deposition, suppressed the expression of EMT markers in mouse kidneys and HK-2 cells, decreased inflammatory cytokine release, and attenuated NF-κB pathway activation. Sevelamer may be a potential therapeutic agent for the treatment of renal fibrosis.

Keywords

HK-2 cell; NF-κB; Renal fibrosis; Sevelamer.

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