TNF-α-mediated podocyte injury via the apoptotic death receptor pathway in a mouse model of IgA nephropathy

Abstract

Background IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide and it is characterized by mesangial IgA deposits. Proteinuria is a common clinical feature of IgAN, which has a critical connection to podocyte injury and has been used as a clinical prognostic factor for IgAN. Evidence has shown that TNF-α released from mesangial cells may lead to podocyte apoptosis. Methods Forty male BALB/c mouse were randomly divided into the control group and IgAN group. A mice model of IgAN was developed by oral administration of bovine serum albumin (BSA) combined with Staphylococcus Enterotoxin B (SEB) tail vein injection. Urinary protein concentrations, renal function, renal morphological, IgA deposition, apoptosis situation, and the mRNA and protein expression of nephrin, podocin, TNF-α, TNFR1, caspase-8 and caspase-3, were detected after 12 weeks. Results BSA and SEB can successfully establish an IgAN mouse model, and the main pathological changes are the IgA immune complex deposition in the mesangial area. The gene and protein expression levels of nephrin and podocin were found to be downregulated, and death receptor pathway-related indicators were upregulated, and they were involved in TNF-α-activated podocyte injury and apoptosis in IgAN mice. Conclusion TNF-α may play an important role in the pathogenesis of podocyte apoptosis in IgAN, and its effects may be mediated through the apoptotic death receptor pathway.

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

“…TNF-α from mesangial cells increases TNF-α synthesis and expression level of TNF receptor 2 (TNFR2) on podocytes, which enhances IL-6 synthesis to induce podocyte apoptosis ( 87 ) and activates the inflammatory response of podocytes ( 57 ) via TNFR1 and TNFR2, respectively. TNF-α-induced podocyte apoptosis was also detected to be associated with increased expression of caspase-3 in renal tissue of mouse model ( 88 ), suggesting TNF-α might induce podocyte apoptosis through TNFR1-/caspase-8/caspase-3 death pathway. Another cell culture experiment demonstrated that TNF-α might induce podocyte apoptosis and foot process effacement through the NF-κB signaling pathway ( 7 ).…”