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

MBG促进尿钠排泄，但引起血管收缩并通过PKC依赖性抑制Fli-1（一种转录因子和胶原合成的负调节因子）诱导纤维化。我们假设，血管平滑肌细胞（VSMC）从老年大鼠由于下调ANP/cGMP/PKG依赖的信号转导将表现出更高的敏感性MBG的促纤维化作用。与年轻（3个月大）大鼠相比，老年（24个月大）Sprague-Dawley大鼠对急性NaCl负荷的反应表现出过度的MBG（5.4 ± 0.4 pmol/hr vs.1.9 ± 0.2 pmol/hr; P <0.01）和升压反应（29 vs.15 mmHg; P<0.01），以及更大的主动脉NKA抑制。老年大鼠血管PKG 1和Fli-1水平明显降低。在离体条件下，1 nmol/LANP可阻断MBG对年轻大鼠血管NKA的抑制作用，但对老年大鼠无此作用。1 nmol/L的MBG可诱导幼年大鼠VSMC Fli-1表达下调，前胶原-1和胶原-1水平升高1.5倍，而1 nmol/L的ANP可阻断这种作用。1 nmol/LMBG使Fli-1降低60%，使胶原-1增加1.6倍（P<0.01）。在老年大鼠VSMC中，ANP不能对抗MBG的促纤维化作用。年轻大鼠VSMC中PKG-1基因的沉默与VSMC对MBG促纤维化作用的敏感性显著增加相关;在这种情况下，1 nmol/L MBG使胶原-1水平增加2.5倍（P<0.01）。这些结果表明，年龄相关的血管PKG 1水平的降低和cGMP信号转导的下降导致ANP对抗MBG诱导的NKA抑制和纤维化的能力丧失。PKG 1沉默模拟衰老对VSMC对强心类固醇促纤维化作用敏感性的影响

MBG promotes natriuresis, but causes vasoconstriction and induces fibrosis via PKC&#61540;-dependent inhibition of Fli-1, a transcription factor and a negative regulator of collagen synthesis. We hypothesized that vascular smooth muscle cells (VSMC) from aged rats due to down-regulation of ANP/cGMP/PKG-dependent signaling would exhibit heightened sensitivity to the pro-fibrotic effect of MBG. In response to acute NaCl loading, aged (24-month old) Sprague-Dawley rats exhibited exaggerated MBG (5.40.4 vs. 1.90.2 pmol/hr; P<0.01) and pressor responses (29 vs. 15 mmHg; P<0.01), as well as greater inhibition of NKA in aorta as compared to young (3-month old) rats. Levels of vascular PKG1 and Fli-1 in aged rats were markedly reduced. In vitro, 1 nmol/L ANP prevented inhibition of vascular NKA by MBG in young, but not in the aged rats. In VSMC from young rats, 1 nmol/L MBG induced down-regulation of Fli-1 and a 1.5-fold increase in the levels of procollagen-1 and collagen-1, and 1 nmol/L ANP blocked this effect. In aged rats, levels of PKG-1 and Fli-1 in VSMC were markedly reduced vs. young rats, and 1 nmol/L MBG decreased Fli-1 (60%) and increased level of collagen-1 1.6-fold (P<0.01). In VSMC from aged rats, ANP failed to oppose the pro-fibrotic effect of MBG. Silencing of the PKG-1 gene in VSMC from young rats was associated with a marked increase in the sensitivity of VSMC to the pro-fibrotic effect of MBG; in this setting 1 nmol/L MBG increased levels of collagen-1 2.5-fold (P<0.01). These results demonstrate that the age-associated reduction in vascular PKG1 levels and resultant decline in cGMP signaling lead to the loss of ability of ANP to oppose MBG-induced inhibition of NKA and fibrosis. Silencing of PKG1 mimics effects of aging with respect to sensitivity of VSMC to pro-fibrotic action of cardiotonic steroids.