Tumor necrosis factor-α receptor type 1, not type 2, mediates its acute responses in the kidney

Castillo A, Islam MT, Prieto MC, Majid DS. Tumor necrosis factor-alpha receptor type 1, not type 2, mediates its acute responses in the kidney. Am J Physiol Renal Physiol 302: F1650-F1657, 2012. First published March 28, 2012; doi: 10.1152/ajprenal.00426.2011.-Acute administration of tumor necrosis factor-alpha (TNF-alpha) resulted in decreases in renal blood flow (RBF) and glomerular filtration rate (GFR) but induced diuretic and natriuretic responses in mice. To define the receptor subtypes involved in these renal responses, experiments were conducted to assess the responses to human recombinant TNF-alpha (0.3 ng.min(-1).g body wt(-1) iv infusion for 75 min) in gene knockout (KO) mice for TNF-alpha receptor type 1 (TNF alpha R1 KO, n = 5) or type 2 (TNF alpha R2 KO, n = 6), and the results were compared with those obtained in corresponding wild-type [WT (C57BL/6), n = 6] mice. Basal levels of RBF (PAH clearance) and GFR (inulin clearance) were similar in TNF alpha R1 KO, but were lower in TNF alpha R1 R2 KO, than WT mice. TNF-alpha infusion in WT mice decreased RBF and GFR but caused a natriuretic response, as reported previously. In TNF alpha R1 KO mice, TNF-alpha infusion failed to cause such vasoconstrictor or natriuretic responses; rather, there was an increase in RBF and a decrease in renal vascular resistance. Similar responses were also observed with infusion of murine recombinant TNF-alpha in TNF alpha R1 KO mice (n = 5). However, TNF-alpha infusion in TNF alpha R2 KO mice caused changes in renal parameters qualitatively similar to those observed in WT mice. Immunohistochemical analysis in kidney slices from WT mice demonstrated that while both receptor types were generally located in the renal vascular and tubular cells, only TNF alpha R1 was located in vascular smooth muscle cells. There was an increase in TNF alpha R1 immunoreactivity in TNF alpha R2 KO mice, and vice versa, compared with WT mice. Collectively, these functional and immunohistological findings in the present study demonstrate that the activation of TNF alpha R1, not TNF alpha R2, is mainly involved in mediating the acute renal vasoconstrictor and natriuretic actions of TNF-alpha.