Molecular insight in intrarenal inflammation affecting four main types of cells in nephrons in IgA nephropathy

Abstract

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis and the leading cause of kidney failure in the world. The current widely accepted framework for its pathogenesis is the “multi-hit hypothesis.” In this review, we mainly discussed the intrarenal inflammation in IgAN, which is initiated by immune complex deposition with complement molecule activation, by focusing on four main types of cells in nephrons including mesangial cells, endothelial cells, podocytes, and tubular epithelial cells (TECs). Galactose-deficient IgA1 (Gd-IgA1)-containing immune complexes deposit in the mesangium and activate complement molecules and mesangial cells. Activation of mesangial cells by Gd-IgA1 deposition with enhanced cellular proliferation, extracellular matrix (ECM) expansion, and inflammatory response plays a central role in the pathogenesis of IgAN. Regional immune complex deposition and mesangial–endothelial crosstalk result in hyperpermeability of endothelium with loss of endothelial cells and infiltration barrier proteins, and recruitment of inflammatory cells. Podocyte damage is mainly derived from mesangial–podocyte crosstalk, in which tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), renin-angiotensin-aldosterone system (RAAS), and micro-RNAs are the major players in podocyte apoptosis and disorganization of slit diaphragm (SD) related to proteinuria in patients with IgAN. In addition to filtrated proteins into tubulointerstitium and mesangial–tubular crosstalk involved in the injury of TECs, retinoic acid has been discovered innovatively participating in TEC injury.

Understanding the podocyte immune responses in proteinuric kidney diseases: from pathogenesis to therapy

“…Cellular crosstalk is a fundamental process of intercellular signaling and interaction that exerts a significant influence on the behavior and function of various cells. This dynamic communication can occur between identical cell types or across different cell types ( 45 ). The interaction between other cells in the glomerulus and podocytes is critical in the development of glomerular diseases.Research has demonstrated a correlation between mitochondrial oxidative stress in glomerular endothelial cells and an increased expression of Endothelin-1 (Edn1) along with its receptor, Endothelin-1 receptor A (Ednra) ( 46 ).…”

Efficacy and safety of biologic agents for IgA nephropathy: A protocol for systematic review and meta-analysis

“…Subsequently, they generate IgG autoantibodies targeting terminal N-acetylgalactosamine (GalNAc) residues, leading to the formation of IgG-Gd-IgA1 immune complexes primarily deposited in the mesangial region of glomeruli. This triggers complement molecule activation and initiates inflammatory responses, ultimately resulting in disease development [16][17][18][19][20]. Biologic agents targeting immune pathogenesis offer a novel therapeutic approach for controlling IgAN progression by depleting or regulating B cells, plasma cells, alternate or lectin pathways involved in Gd-IgA1 production [21][22][23][24][25][26].…”

Deciphering roles of protein post-translational modifications in IgA nephropathy progression and potential therapy

“…Genetics, epigenetics and environmental factors have been considered to be involved in IgAN development, although the exact molecular mechanisms of IgAN have not been fully elucidated [14][15][16]. Integration of genomic data with other omics data, such as AGING metabolomics and transcriptomics, can explore the genetic changes of IgAN pathogenesis [17].…”