Tumor Necrosis Factor-α and Kidney Function: Experimental Findings in Mice

Abstract

TNF-α has been implicated in the pathogenesis of hypertension and renal injury. However, the direct effect of TNF-α on the regulation of renal hemodynamic and excretory function was not examined until recently. In a series of studies in our laboratory, the renal responses to acute intravenous infusion of TNF-α (0.33 ng/g/min; for 75 min) were evaluated in anesthetized mice. Renal blood flow (RBF) and glomerular filtration rate (GFR) were determined by PAH and inulin clearances. The urine was collected from a cannula inserted into the bladder. TNF-α infusion alone (n = 7) caused marked decreases of 25±5% in RBF and 41±7% in GFR without altering systemic arterial pressure or heart rate. However, interestingly there were marked increases in urine flow (70±21%) and sodium excretion (106±18%) in response to TNF-α administration. These responses were prevented in mice pretreated with TNF-α blocker, etanercept. However, while the diuretic and natriuretic responses to TNF-α remained intact, RBF response was further enhanced in mice pretreated with NO synthase inhibitor, nitro-L-arginine methyl ester (L-NAME) but completely abolished, rather increased in mice pretreated with superoxide (O2 −) scavenger, tempol. The diuretic and natriuretic responses to TNF-α are only prevented in mice pretreated with combined amiloride and bendroflumethiazide that would block distal tubular sodium transport. These data suggest that TNF-α induces renal vasoconstriction and hypofiltration via enhancing the activity of O2 − and thus reducing the bioactivity of NO. The natriuretic response to TNF-α is related to its direct inhibitory action on distal tubular sodium transport.