TGF-β1/IL-11 positive loop between renal tubular epithelial cell and fibroblast promotes the ectopic calcification of renal interstitial fibroblasts in rats

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Randall's plaque (RP) is one of the key causes of calcium oxalate (CaOx) kidney stones formation and recurrence characterized by osteogenic differentiation and fibrosis in renal papilla area. Previous studies have found that IL-11 could promote the osteogenesis of fibroblasts and function as a pro-fibrotic cytokine. Moreover, IL-11 expression is increased in RP tissues. This study aims to explore the role and underlying mechanism of IL-11 in the regulation of RP formation. IL-11 levels were significantly upregulated in RP tissues, urine, and serum of CaOx kidney stones patients. IL-11 could promote the ectopic calcification of renal fibroblasts via activating ERK1/2 and JNK signaling pathways. In co-culture system, CaOx crystals could induce a TGF-β1/IL-11 positive feedback loop between renal epithelial cells and fibroblasts, consequently enhance the ectopic calcification of renal fibroblasts. In vivo, anti-IL-11 neutralizing antibodies significantly inhibited hyperoxaluria-induced osteogenic differentiation, fibrosis, and CaOx crystal depositions in the kidney. Our findings highlight a critical role of IL-11 in RP formation and emphasize the TGF-β1/IL-11 positive feedback loop in renal fibroblast calcification, providing new insights into the pathogenesis of RP from the perspective of intercellular communication.