细胞生物学
足细胞
TLR4型
旁分泌信号
串扰
炎症
肾
炎症体
肾小球
信号转导衔接蛋白
信号转导
化学
受体
生物
内科学
内分泌学
免疫学
肾小球肾炎
医学
生物化学
物理
光学
蛋白尿
作者
Rajiv Rana,Jayakumar Manoharan,Ahmed Elwakiel,Silke Zimmermann,Jonathan A. Lindquist,Dheerendra Gupta,Moh’d Mohanad Al‐Dabet,Ihsan Gadi,Jörg Fallmann,Kunal Kumar Singh,Anubhuti Gupta,Ronald Biemann,Sabine Brandt,Bekas Alo,P. Kluge,Ravindra Garde,Christina Lamers,Khurrum Shahzad,Georg Künze,Shruti Kohli,Peter R. Mertens,Berend Isermann
标识
DOI:10.1016/j.kint.2023.09.014
摘要
Glomerular-tubular crosstalk within the kidney has been proposed, but the paracrine signals enabling this remain largely unknown. The cold-shock protein Y-box binding protein 1 (YBX1) is known to regulate inflammation and kidney diseases but its role in podocytes remains undetermined. Therefore, we analyzed mice with podocyte specific Ybx1 deletion (Ybx1ΔPod). Albuminuria was increased in unchallenged Ybx1ΔPod mice, which surprisingly was associated with reduced glomerular, but enhanced tubular damage. Tubular toll-like receptor 4 (TLR4) expression, node-like receptor protein 3 (NLRP3) inflammasome activation and kidney inflammatory cell infiltrates were all increased in Ybx1ΔPod mice. In vitro, extracellular YBX1 inhibited NLRP3 inflammasome activation in tubular cells. Co-immunoprecipitation, immunohistochemical analyses, microscale cell-free thermophoresis assays, and blunting of the YBX1-mediated TLR4-inhibition by a unique YBX1-derived decapeptide suggests a direct interaction of YBX1 and TLR4. Since YBX1 can be secreted upon post-translational acetylation, we hypothesized that YBX1 secreted from podocytes can inhibit TLR4 signaling in tubular cells. Indeed, mice expressing a non-secreted YBX1 variant specifically in podocytes (Ybx1PodK2A mice) phenocopied Ybx1ΔPod mice, demonstrating a tubular-protective effect of YBX1 secreted from podocytes. Lipopolysaccharide-induced tubular injury was aggravated in Ybx1ΔPod and Ybx1PodK2A mice, indicating a pathophysiological relevance of this glomerular-tubular crosstalk. Thus, our data show that YBX1 is physiologically secreted from podocytes, thereby negatively modulating sterile inflammation in the tubular compartment, apparently by binding to and inhibiting tubular TLR4 signaling. Hence, we have uncovered an YBX1-dependent molecular mechanism of glomerular-tubular crosstalk.
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