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

MBG是一种内源性Na/K-ATP酶（NKA）抑制剂，通过抑制肾小管NKA促进尿钠排泄，但可能通过抑制血管系统中的NKA引起血管收缩。最近，我们证明，ANP，通过cGMP/PKG-2依赖性磷酸化的肾α-1 NKA，敏感的肾钠泵MBG，并可能加强利钠作用的MBG。相反，在血管系统中，ANP通过PKG-1依赖性机制减少NKA磷酸化，并可能抵消MBG诱导的过度血管收缩。由于衰老与cGMP/PKG信号的下调有关，我们假设在老年大鼠中，ANP不会增强MBG的肾脏作用，也不会对抗MBG的血管作用。在年轻（3个月大）和老年（24个月大）Sprague-Dawley大鼠中，我们比较了收缩压（BP）、尿钠排泄、肾髓质和血管肌膜中的NKA活性、急性NaCl负荷（20%，2.5 ml/kg，腹腔内）后的MBG和α-ANP水平以及MBG和α-ANP对NKA的体外相互作用。与年轻大鼠相比，NaCl负荷的老年大鼠表现出更大的MBG反应（1.420.20 vs.5.960.89和1.630.21 vs.3.020.47 pmoles/hr，P<0.01），血压升高更大（31 vs. 14 mm Hg，P<0.01），并且在大鼠中NKA的抑制更大（32 vs. 2%; P<0.01），尿钠排泄减少（2.00.1 vs.0.17 ± 0.02和2.90 ± 0.1 vs.0.23 ± 0.03 mmol/kg/hr; P<0.01），肾髓质NKA抑制较少（25 vs. 42%; P<0.05），在α-ANP和cGMP水平存在可比变化的情况下。老年大鼠主动脉PKG-1和肾脏PKG-2水平明显降低，而肾脏PDE-V水平升高。1 nmol/L α-ANP对老年大鼠主动脉肌膜和肾髓质α-1 NKA磷酸化水平无明显影响。因此，在老年动物中，低浓度的α-ANP不增强MBG诱导的肾髓质NKA抑制，也不降低MBG对主动脉肌膜NKA的作用。我们的研究结果表明，在老年大鼠中，cGMP/PKG依赖性信号转导的下调是ANP调节MBG对肾和血管钠泵的作用的转变的基础，这促进了盐敏感性。

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.