Aging and interaction of natriuretic factors on renal and vascular sodium pump

MBG是一种内源性Na/K-ATPase(NKA)抑制剂，通过抑制肾小管NKA促进钠尿，但也可能通过抑制血管内NKA而引起血管收缩。最近我们证实，ANP通过依赖cGMP/PKG-2的肾α-1 NKA的磷酸化，使肾钠泵对MBG增敏，并可能增强MBG的利钠作用。相反，在血管系统，ANP通过依赖PKG-1的机制减少NKA的磷酸化，并可能抵消MBG引起的过度血管收缩。由于衰老与cGMP/PKG信号的下调有关，我们假设在老年大鼠，ANP不会增强MBG的肾脏效应，也不会对抗MBG的血管效应。我们比较了青年(3月龄)和老年(24月龄)SD大鼠在急性盐负荷(20%，2.5ml/kg)后的血压、尿钠、肾髓质和血管肌膜NKA活性、MBG和α-ANP水平以及MBG和α-ANP的体外相互作用。与青年大鼠相比，盐负荷老年大鼠表现出更大的MBG反应(1.420.20比5.960.89和1.630.21比3.020.47 pmoles/hr，P&lt；0.01)，更高的血压升高(31比14 mm Hg，P&lt；0.01)，更强的抑制NKA(比2%；P&lt；0.01)，更少的钠尿(2.00.1比0.170.02和2.90.1比0.230.03 mmol/kg/hr，P&lt；0.01)；在α-ANP和cGMP水平有类似变化的情况下，肾髓质中NKA的抑制程度较低(25vs.42%；P&lt；0.05)。老年大鼠主动脉和肾脏中PKG-1和PKG-2水平显著降低，而肾脏PDE-V水平显著升高。在老年大鼠，1nmol/Lα-心钠素不影响主动脉肌膜和肾髓质中α-1NKA的磷酸化水平。因此，在老年动物中，低浓度的α-ANP不能增强MBG对肾髓质NKA的抑制作用，也不能降低MBG对主动脉肌膜NKA的抑制作用。我们的结果表明，在老年大鼠，cGMP/PKG依赖的信号通路下调是心钠素调节MBG对肾脏和血管钠泵影响的基础，从而促进了盐敏感性。

MBG, an endogenous Na/K-ATPase (NKA) inhibitor, promotes natriuresis via inhibition of renotubular NKA, but may cause vasoconstriction via inhibition of the NKA in the vasculature. Recently we demonstrated that ANP, via cGMP/PKG-2-dependent phosphorylation of renal alpha-1 NKA, sensitizes renal sodium pumps to MBG and may potentiate natriuretic action of MBG. In the vasculature, on the opposite, ANP, via PKG-1 dependent mechanism, reduces NKA phosphorylation and may offset the excessive vasoconstriction induced by MBG. Since aging is associated with a down-regulation of cGMP/PKG signaling, we hypothesized that in aged rats, ANP would not potentiate renal effects of MBG and would not oppose vascular effects of MBG. In young (3 month old) and aged (24 months old) Sprague-Dawley rats, we compared systolic blood pressure (BP), natriuresis, NKA activity in renal medulla and in vascular sarcolemma, and levels of MBG and alpha-ANP following acute NaCl loading (20%, 2.5 ml/kg, intraperitoneally), and the in vitro interactions of MBG and a-ANP on the NKA. As compared to young rats, NaCl-loaded aged rats exhibited greater MBG response (1.420.20 vs. 5.960.89 and 1.630.21 vs. 3.020.47 pmoles/hr, P<0.01), greater BP elevation (31 vs. 14 mm Hg, P<0.01) and greater inhibition of NKA in aortae (32 vs. 2%; P<0.01), less natriuresis (2.00.1 vs. 0.170.02 and 2.90.1 vs. 0.230.03 mmol/kg/hr; P<0.01) and less inhibition of NKA in renal medulla (25 vs. 42 %; P<0.05) in the presence of comparable changes in alpha-ANP and cGMP levels. Levels of PKG-1 in aorta and PKG-2 in the kidney in aged rats were markedly reduced, while levels of PDE-V in the kidney were increased. In aged rats, 1 nmol/L alpha-ANP did not affect level of alpha-1 NKA phosphorylation in aortic sarcolemma and renal medulla. Accordingly, in aged animals low concentrations of alpha-ANP did not potentiate MBG-induced inhibition of NKA from renal medulla and did not reduce effect of MBG on the NKA from aortic sarcolemma. Our results demonstrate that in aged rats, down-regulation of cGMP/PKG dependent signaling underlies a shift in ANP modulation of the effect of MBG on renal and vascular sodium pump, which promotes salt-sensitivity.