Abstract：
Podocytes maintain renal filtration integrity when the glomerular filtration barrier (GFB) is integrated. Impairment or attrition of podocytes, leading to compromised GFB permeability, constitutes the primary etiology of proteinuria and is a hallmark pathological feature of diabetic nephropathy (DN). This study centers on Heterogeneous Nuclear Ribonucleoprotein I (HNRNP I), an RNA-binding protein, delineating its role in facilitating DN-induced renal damage by modulating podocyte health. Comparative analyses in renal biopsy specimens from DN patients and high-glucose-challenged podocyte models in vitro revealed a marked downregulation of HNRNP I expression relative to normal renal tissues and podocytes. In vitro assays demonstrated that high-glucose conditions precipitated a significant reduction in podocyte viability and an escalation in markers indicative of apoptosis. Conversely, HNRNP I overexpression was found to restore podocyte viability and attenuate apoptotic indices. IRAK1, a gene encoding a protein integral to inflammatory signaling, was shown to interact with HNRNP I, which promotes IRAK1 degradation. This interaction culminates in suppressing the PI3K/AKT/mTOR signaling pathway, thereby diminishing podocyte apoptosis and mitigating renal damage in DN. This investigation unveils the mechanistic role of HNRNP I in DN for the first time, potentially informing novel therapeutic strategies for DN renal impairment.
摘要：
当肾小球滤过屏障(GFB)整合时,足细胞维持肾滤过完整性。足细胞的减损或减员，导致GFB渗透性受损，构成蛋白尿的主要病因，是糖尿病肾病（DN）的标志性病理特征。本研究以异质核核糖核蛋白I（HNRNPI）为中心，一种RNA结合蛋白，描述其在通过调节足细胞健康促进DN诱导的肾损伤中的作用。来自DN患者的肾活检标本和体外高糖攻击的足细胞模型的比较分析显示，相对于正常肾组织和足细胞，HNRNPI表达明显下调。体外测定表明，高葡萄糖条件导致足细胞活力的显着降低和指示凋亡的标志物的增加。相反，发现HNRNPI过表达可恢复足细胞活力并减弱凋亡指数。IRAK1，一种编码与炎症信号整合的蛋白质的基因，被证明与HNRNPI相互作用，促进IRAK1降解。这种相互作用最终抑制PI3K/AKT/mTOR信号通路，从而减少足细胞凋亡并减轻DN的肾损伤。这项研究首次揭示了HNRNPI在DN中的机制作用，可能为DN肾功能损害提供新的治疗策略。
