Abstract 246: Interleukin-1 Potentiates Renal Sodium Retention in Angiotensin Ii-dependent Hypertension by Preventing No-mediated Inhibition of the Na+-k+-2cl- Cotransporter
The current studies define the mechanism through which interleukin-1 receptor (IL-1R) activation exacerbates angiotensin (Ang) II-induced hypertension. We previously reported that IL-1R-deficient (KO) mice had attenuated elevations in blood pressure (BP) vs. wild-types (WT) in our hypertension model of uni-nephrectomy followed by 4 wks of Ang II infusion. As the IL-1 receptor modulates macrophage function, we blindly counted F4/80+ macrophages in KO and WT kidneys after 4 wks of Ang II. Compared to WTs, the KO kidneys contained more macrophages (13.6±1.7 vs. 17.9±0.8 per HPF; p=0.03) and had higher mRNA levels of the macrophage cytokine iNOS (1.0±0.2 vs. 1.7±0.3 au; p<0.05) that drives nitric oxide (NO) generation. As NO regulates renal sodium (Na) handling, we conducted Na balance studies during Ang II infusion. Over days 10-15 of Ang II during which WT and KO BPs separated, the KOs entered negative Na balance while that of the WTs remained positive (-16.8±16.8 vs. 34.8±7.5 μmol/day, p=0.01). Thus, the KOs were protected from Ang II-induced Na retention. To confirm that preserved NO bioavailability in the Ang II-infused KOs led to their lower blood pressures vs. WTs, we blocked NO generation in the groups with L-NAME starting on day 7 of Ang II when the WT and KO BPs were 179±3 vs. 165±6 mm Hg (p<0.01), and by day 14, the BPs had converged (186±5 vs. 185±8; p=NS). Thus, NO depletion abrogated the BP difference between groups. As NO is known to regulate activity of the Na-K-2Cl (NKCC2) cotransporter, we measured NKCC2 activity at day 10 of Ang II by quantitating urine (U) Na/Cr 3 hours after an IP injection of 0.5ml saline with or without furosemide (20mg/kg). Following saline injection alone, the KOs had a higher UNa/Cr than the WTs (237±38 vs. 120±14 mmol/mmol; p=0.01) whereas the UNa/Cr’s converged in response to furosemide (481±103 vs. 453±60; p=NS). By contrast, the UNa/Cr’s did not converge following an IP HCTZ challenge to block NCC channels (not shown). Thus, lower levels of NKCC2 activity in the IL-1R KOs protect them from Ang II-induced sodium retention. In sum, our studies define a novel immune-mediated mechanism of hypertension in which Ang II-induced stimulation of IL-1 signaling promotes renal sodium retention by limiting NO-mediated inhibition of NKCC2 activity.
- © 2013 by American Heart Association, Inc.