Effects of tumor necrosis factor-α inhibition on kidney fibrosis and inflammation in a mouse model of aristolochic acid nephropathy

Abstract

Tumor necrosis factor (TNF)-α is a potent mediator of inflammation and is involved in the pathophysiology of chronic kidney disease (CKD). However, the effects of TNF-α inhibition on the progression of kidney fibrosis have not been fully elucidated. We examined the effects of TNF-α inhibition by etanercept (ETN) on kidney inflammation and fibrosis in mice with aristolochic acid (AA) nephropathy as a model of kidney fibrosis. C57BL/6 J mice were administered AA for 4 weeks, followed by a 4-week remodeling period. The mice exhibited kidney fibrosis, functional decline, and albuminuria concomitant with increases in renal mRNA expression of inflammation- and fibrosis-related genes. The 8-week ETN treatment partially but significantly attenuated kidney fibrosis and ameliorated albuminuria without affecting kidney function. These findings were accompanied by significant suppression of interleukin (IL)-1β, IL-6, and collagen types I and III mRNA expression. Moreover, ETN tended to reduce the AA-induced increase in interstitial TUNEL-positive cells with a significant reduction in Bax mRNA expression. Renal phosphorylated p38 MAPK was significantly upregulated by AA but was normalized by ETN. These findings indicate a substantial role for the TNF-α pathway in the pathogenesis of kidney fibrosis and suggest that TNF-α inhibition could become an adjunct therapeutic strategy for CKD with fibrosis.

Effects of Etanercept on TNF-α Inhibition in Rats with Adenine-Induced Chronic Kidney Disease

“…Although, some studies showed that treatments with TNF- α inhibitors have shown protective effects in the models of acute kidney injury (AKI) such as ischemia/reperfusion (I/R) injury [ 23 , 24 ], but there are few evidences about the effects of TNF- α blockers in the models of chronic kidney damage [ 25 , 26 ]. Recently, a study of an 8-week ETA treatment in mice with aristolochic acid (AA) nephropathy as a model of kidney fibrosis found that ETA partially but significantly attenuated kidney fibrosis and ameliorated albuminuria without affecting kidney function [ 14 ]. As previously mentioned, in our study, although we found an improvement in some renal function parameters and observed less tissue damage, we did not find a significant reduction in renal fibrosis with ETA treatment.…”

“…Etanercept (Enbrel® 50 mg) was administrated by sc injection at a dose of 2 mg/kg, 3 times per week one hour before the dose of Ad. This dose was selected as an average of previous studies reporting antifibrotic effects of ETA [ 12 – 14 ].…”

“…It is a fusion protein that is composed of the extracellular ligand-binding portion of human p75 TNFR linked to the Fc portion of human IgG1 and acts as a “TNF decoy receptor” by inhibiting the binding of soluble TNF- α to its cell surface receptor [ 11 ]. Some studies have reported the effectiveness of ETA-reducing inflammation in different pathologies related with an exacerbated immune response or fibrosis [ 12 – 14 ]. However, the impact of TNF- α inhibition on CKD progression is not fully elucidated.…”

Research Progress of Chinese Herbal Medicine Intervention in Renal Interstitial Fibrosis

“…These signaling pathways further promote the activation of TNF-α by increasing the extent of many inflammatory factors. Serum TNF-α standard is closely related to the severity of renal injury ( Liu Y. et al, 2021 ; Taguchi et al, 2021 ).…”

Aristolochic acid I induces proximal tubule injury through ROS/HMGB1/mt DNA mediated activation of TLRs

“…Kidney injury and fibrosis are predictable features of AAN, such that it is now used as a kidney injury/fibrosis model in vitro and in vivo studies 11–13 . Although studies have provided considerable insights into mechanisms of AA‐induced nephropathy, the pathophysiology of AAN remains incompletely understood 14–19 …”