足细胞NPRC缺乏减轻糖尿病小鼠的肾小球纤维化

Podocyte NPRC Deficiency Attenuates Glomerular Fibrosis in Diabetic Mice.

作者信息

Wang Xinlu, Li Jingwei, Ma Wenlei, Meng Linlin, Lu Yue, Song Jiawei, Chen Sizhe, Zhen Junhui, Yu Xiao, Xi Bo, Xu Feng, Zhang Wencheng, Zhang Yun, Sui Wenhai, Zhang Cheng

机构信息

Department of Cardiology, State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, China. (X.W., J.L., W.M., L.M., Y.L., J.S., S.C., W.Z., Y.Z., W.S., C.Z.).

Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, China (J.Z.).

出版信息

Circ Res. 2025 Jun 25. doi: 10.1161/CIRCRESAHA.124.325702.

DOI:10.1161/CIRCRESAHA.124.325702

PMID:40557490

Abstract

BACKGROUND

Renal fibrosis plays a key role in the progression of diabetic kidney disease (DKD). Although the renal protective effects of NPs (natriuretic peptides) were reported, the role of NPR (natriuretic peptide receptor) C in modulating renal fibrosis in DKD remains unclear.

METHODS

The expression and function of NPRC in DKD were investigated using human renal biopsies and a diabetic mouse model. Podocyte-specific NPRC knockout mice were developed to explore the role of NPRC in renal fibrosis. Gene and protein analyses such as histological staining, serum chemical assay, mass spectrometry analysis, ELISA, and Western blot were performed to examine the impact of NPRC deficiency on TGF-βR (transforming growth factor-β receptor) 2 expression, recycling, Smad2/3 signaling, and the overall renal structure and function.

RESULTS

Increased expression of NPRC was observed in both patients with DKD and DKD mice. Podocyte-specific NPRC knockout mice showed reduced glomerular fibrosis and improved podocyte injury and renal function compared with wild-type controls. Notably, NPRC knockdown resulted in decreased COL (collagen) synthesis in podocytes. Molecular biology studies revealed that NPRC deficiency led to decreased recycling and increased degradation of TGF-βR2, thus suppressing the TGF-β (transforming growth factor-β)1/Smad pathway.

CONCLUSIONS

NPRC plays a detrimental role in the progression of DKD by enhancing TGF-βR2 expression and TGF-β1/Smad signaling pathway. Podocyte-specific NPRC deficiency not only attenuates glomerular fibrosis but also improves renal function, suggesting that NPRC may serve as a promising therapeutic target for managing diabetic renal fibrosis.

摘要

背景

肾纤维化在糖尿病肾病（DKD）进展中起关键作用。尽管已报道利钠肽（NPs）具有肾脏保护作用，但利钠肽受体（NPR）C在调节DKD肾纤维化中的作用仍不清楚。

方法

利用人肾活检组织和糖尿病小鼠模型研究DKD中NPRC的表达和功能。构建足细胞特异性NPRC基因敲除小鼠，以探究NPRC在肾纤维化中的作用。进行组织学染色、血清化学检测、质谱分析、酶联免疫吸附测定（ELISA）和蛋白质印迹等基因和蛋白质分析，以检查NPRC缺乏对转化生长因子-β受体（TGF-βR）2表达、再循环、Smad2/3信号传导以及整体肾脏结构和功能的影响。

结果

在DKD患者和DKD小鼠中均观察到NPRC表达增加。与野生型对照相比，足细胞特异性NPRC基因敲除小鼠的肾小球纤维化减轻，足细胞损伤和肾功能改善。值得注意的是，NPRC敲低导致足细胞中胶原蛋白（COL）合成减少。分子生物学研究表明，NPRC缺乏导致TGF-βR2再循环减少和降解增加，从而抑制转化生长因子-β（TGF-β）1/Smad途径。