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

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.