Complement factor B in high glucose–induced podocyte injury and diabetic kidney disease

Qingmiao Lu,Xiaoli Sun,Mengru Gu,Chunsun Dai,Kai Cao,Yan Liang,Xian Xue,Allan Zijian Zhao,Qing Hou

doi:10.1172/jci.insight.147716

Abstract

The role and mechanisms for upregulating complement factor B (CFB) expression in podocyte dysfunction in diabetic kidney disease (DKD) are not fully understood. Here, analyzing Gene Expression Omnibus GSE30528 data, we identified genes enriched in mTORC1 signaling, CFB, and complement alternative pathways in podocytes from patients with DKD. In mouse models, podocyte mTOR complex 1 (mTORC1) signaling activation was induced, while blockade of mTORC1 signaling reduced CFB upregulation, alternative complement pathway activation, and podocyte injury in the glomeruli. Knocking down CFB remarkably alleviated alternative complement pathway activation and DKD in diabetic mice. In cultured podocytes, high glucose treatment activated mTORC1 signaling, stimulated STAT1 phosphorylation, and upregulated CFB expression, while blockade of mTORC1 or STAT1 signaling abolished high glucose–upregulated CFB expression. Additionally, high glucose levels downregulated protein phosphatase 2Acα (PP2Acα) expression, while PP2Acα deficiency enhanced high glucose–induced mTORC1/STAT1 activation, CFB induction, and podocyte injury. Taken together, these findings uncover a mechanism by which CFB mediates podocyte injury in DKD.

Highlights

Millions of people worldwide have diabetes mellitus, and approximately 20%–40% of them develop diabetic kidney disease (DKD) [1,2,3,4]
While the complement system is typically activated through the classic pathway and the lectin pathway, the Complement factor B (CFB)-regulated alternative pathway plays a significant role in the pathogenesis of kidney diseases, such as lupus nephritis [13, 14], atypical hemolytic uremic syndrome [15, 16], complement 3 (C3) glomerulopathies (GNs) [17], anti-neutrophil cytoplasmic antibody–associated (ANCA-associated) GN [18, 19], autosomal dominant polycystic kidney disease (ADPKD) [20], IgA nephropathy [21], and immune rejection after renal transplantation [22]
The results revealed genes enriched in complement system activation via Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis, such as C3, C1QB, CLU, C7, C1QA, VSIG4, CFB, FGG, ITGB2, VWF, C3AR1, C2, ITGAM, CFD, PROCR, ITGAX, C8G, CD55, CR1, F5, F3, F2R, and PLAT

Summary

Introduction

Millions of people worldwide have diabetes mellitus, and approximately 20%–40% of them develop diabetic kidney disease (DKD) [1,2,3,4]. While the complement system is typically activated through the classic pathway and the lectin pathway, the CFB-regulated alternative pathway plays a significant role in the pathogenesis of kidney diseases, such as lupus nephritis [13, 14], atypical hemolytic uremic syndrome [15, 16], complement 3 (C3) glomerulopathies (GNs) [17], anti-neutrophil cytoplasmic antibody–associated (ANCA-associated) GN [18, 19], autosomal dominant polycystic kidney disease (ADPKD) [20], IgA nephropathy [21], and immune rejection after renal transplantation [22]. The regulatory mechanisms of activating the alternative complement pathway in podocytes in DKD remain to be determined

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