Molecular Profiling in IgA Nephropathy and Focal and Segmental Glomerulosclerosis

Abstract

The aim of the study was to characterize by molecular profiling two glomerular diseases: IgA nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS) and to identify potential molecular markers of IgAN and FSGS progression. The expressions of 90 immune-related genes were compared in biopsies of patients with IgAN (n=33), FSGS (n=17) and in controls (n=11) using RT-qPCR. To identify markers of disease progression, gene expression was compared between progressors and non-progressors in 1 year follow-up. The results were verified on validation cohort of patients with IgAN (n=8) and in controls (n=6) using laser-capture microdissection, that enables to analyze gene expression separately for glomeruli and interstitium. In comparison to controls, patients with both IgAN and FSGS, had lower expression of BAX (apoptotic molecule BCL2-associated protein) and HMOX-1 (heme oxygenase 1) and higher expression of SELP (selectin P). Furthermore, in IgAN higher expression of PTPRC (protein-tyrosine phosphatase, receptor-type C) and in FSGS higher expression of BCL2L1 (regulator of apoptosis BCL2-like 1) and IL18 compared to control was observed. Validation of differentially expressed genes between IgAN and controls on another cohort using laser-capture microdissection confirmed higher expression of PTPRC in glomeruli of patients with IgAN. The risk of progression in IgAN was associated with higher expression EDN1 (endothelin 1) (AUC=0.77) and FASLG (Fas ligand) (AUC=0.82) and lower expression of VEGF (vascular endothelial growth factor) (AUC=0.8) and in FSGS with lower expression of CCL19 (chemokine (C-C motif) ligand 19) (AUC=0.86). Higher expression of EDN1 and FASLG along with lower expression of VEGF in IgAN and lower expression of CCL19 in FSGS at the time of biopsy can help to identify patients at risk of future disease progression.

Review on Inflammation Markers in Chronic Kidney Disease

“…In adult-onset minimal change disease, levels of VCAM and E-selectin were increased and associated with severity of nephrotic syndrome [146]. A multicenter study revealed that IgAN and focal segmental glomerulosclerosis (FSGS) had higher levels of P-selectin than healthy controls [147]. However, in CKD patients with atrial fibrillation, levels of P-selectin and E-selectin did not correlate with eGFR [148].…”

Toll-Like Receptor as a Potential Biomarker in Renal Diseases

“…To fully explain kidney damage in IgAN, it is necessary to fully understand the effects of TLR4 in the development of glomerulopathy, involving both glomerular cells and circulating leukocytes. Studies have shown that the administration of LPS activates TLR4 receptors on mesangial cells, and causes the release of chemokines (CXCs), which promotes neutrophil infusion and the development of glomerulonephritis [114][115][116]. In addition, the IFN-γ and IFN-α responses induced by TLR activation induce overexpression of the B-cell activation factor (BAFF) in dendritic cells, favoring the expansion of B-cells and increasing IgA synthesis [117][118][119][120][121].…”

Emerging Modes of Treatment of IgA Nephropathy

“…We demonstrated association of the progresson of IgAN with polymorphisms of the ET-1 gene [97]. Association of ET-1 expression with the progression of IgAN was also confirmed using molecular profiling [98]. A specific ET-receptor antagonist (FR 139317) was shown to suppress the development of histologic lesions and proteinuria in ddY mice with IgAN [99].…”