Role of TNFR1 and TNFR2 receptors in tubulointerstitial fibrosis of obstructive nephropathy

Unilateral ureteral obstruction (UUO) results in tubulointerstitial fibrosis of the obstructed kidney. In this study, we report the contribution of tumor necrosis factor-α (TNF-α) to the fibrosis that develops after ureteral obstruction. Mice in which individual TNF-α receptors TNFR1 or TNFR2 had been genetically knocked out were used, and results were compared with mice of C57Bl/6 background after 5 days UUO. Both kidneys were removed and examined histologically for changes in interstitial volume (Vv ), collagen IV deposition, α-smooth muscle actin (α-SMA) matrix score, nuclear factor-κB (NF-κB) activity, and TNF-α mRNA levels. We found that the Vv of contralateral unobstructed kidneys averaged ∼7% and was indistinguishable among the three genotypes of mice. Vv of ureteral obstructed kidney of C57Bl/6 mice averaged 33 ± 3.9% after 5 days of UUO. Vv of obstructed kidneys of TNFR1 mice was significantly reduced to 19.4 ± 3.1%, whereas that of TNFR2 mice was significantly decreased to 25.4% ± 4.8%. There was a modest but significant difference between Vv of TNFR1 and TNFR2 ( P < 0.047). Both collagen IV and α-SMA matrix scores were decreased significantly in obstructed kidney of TNFR1 mouse compared with that of C57Bl/6 and TNFR2 mice. Nuclear extracts prepared from kidney cortex were found to have a significant increase in NF-κB binding activity in obstructed kidney compared with contralateral kidney. Individual knockout of the TNFR1 or TNFR2 genes resulted in significantly less NF-κB activation compared with the wild type, with TNFR1 being less than TNFR2 knockout. There was a significant increase in TNF-α mRNA in the kidney with ureteral obstruction in all three genotypes. TNFR1 knockout displayed a significant reduction in amount of TNF-α mRNA induced compared with wild-type or TNFR2 knockout mice. Treatment of TNFR1 knockout mice with an angiotensin converting enzyme inhibitor further decreased Vv and TNF-α mRNA induction, suggesting an interaction of ANG II and TNF-α systems. These results suggest that TNF-α contributes, in part, to changes in interstitial volume, myofibroblast differentiation, and NF-κB activation in the kidney during ureteral obstruction. These changes appear to be mediated through both TNFR1 and TNFR2 gene products with effects through the TNFR1 receptor predominating. Furthermore, ANG II appears to stimulate TNF-α pathophysiological events leading to renal fibrosis.