Valentin J P, Ying W Z, Sechi L A, Ling K T, Qiu C, Couser W G, Humphreys M H
Division of Nephrology, San Francisco General Hospital, University of California 94143, USA.
J Am Soc Nephrol. 1996 Apr;7(4):582-93. doi: 10.1681/ASN.V74582.
Experimental nephrotic syndrome is characterized by abnormal sodium metabolism, reflected in a blunted natriuretic response both to volume expansion and to infused atrial natriuretic peptide (ANP). The studies presented here examined the relationships among plasma ANP concentration and urinary sodium (VNaV) and cyclic GMP excretion (UcGMPV) in vivo, and the responsiveness of isolated glomeruil and inner medullary collecting duct (IMCD) cells to ANP and urodilatin (renal natriuretic peptide; RNP) in vitro in rats with Heymann nephritis, an immunologically mediated model of nephrotic syndrome. Nine to 14 days after Ip injection of anti-Fx1A antiserum, rats were proteinuric and had a blunted natriuretic response to intravenous infusion of isotonic saline (2% body weight, given over 5 min). Thirty min after the onset of the infusion, plasma ANP concentration was increased to the same extent in both normal and nephritic rats, compared with their respective hydropenic controls. Despite this increase, UcGMPV was significantly less in nephritic rats after the saline infusion. Accumulation of cGMP by isolated glomeruil and IMCD cells from nephritic rats after incubation with ANP and RNP was also significantly reduced, compared with normal rats. This difference was not related to differences in either density or affinity of renal ANP receptors, but was abolished when accumulation of cGMP was measured in the presence of 10(-3) M isobutylmethylxanthine or Zaprinast, two different inhibitors of cyclic nucleotide phosphodiesterases (PDE). Infusion of Zaprinast into one renal artery in nephritic rats normalized both the natriuretic response to volume expansion and the increase in UcGMPV from the infused, but not the contralateral, kidney. Furthermore, cGMP-PDE activity was increased in IMCD cell homogenates from nephritic compared with normal rats (388 +/- 32 versus 198 +/- 93 pmol/min per mg protein, P < 0.03). These results indicate that blunted volume expansion natriuresis accompanied by cellular resistance to ANP in vitro occurs in an immunologic model of renal injury. The resistance is not related to an alteration in ANP release or binding to its renal receptors, but is suppressed by PDE inhibitors and is associated with increased renal cGMP. PDE activity, thus suggesting that enhanced cGMP-PDE activity may account for resistance to the natriuretic actions of ANP observed in vivo. This defect may represent the intrinsic sodium transport abnormality linked to sodium retention in nephrotic syndrome.
实验性肾病综合征的特征是钠代谢异常，表现为对容量扩张和静脉输注心房利钠肽（ANP）的利钠反应减弱。本文的研究检测了体内血浆ANP浓度与尿钠排泄（VNaV）及环磷酸鸟苷排泄（UcGMPV）之间的关系，以及在海曼肾炎大鼠（一种免疫介导的肾病综合征模型）中，体外分离的肾小球和髓质内集合管（IMCD）细胞对ANP和尿舒张素（肾利钠肽；RNP）的反应性。腹腔注射抗Fx1A抗血清9至14天后，大鼠出现蛋白尿，对静脉输注等渗盐水（2%体重，5分钟内输注完毕）的利钠反应减弱。输注开始30分钟后，与各自的禁水对照组相比，正常大鼠和肾炎大鼠的血浆ANP浓度升高幅度相同。尽管有这种升高，但盐水输注后肾炎大鼠的UcGMPV明显较低。与正常大鼠相比，肾炎大鼠分离的肾小球和IMCD细胞在与ANP和RNP孵育后cGMP的积累也显著减少。这种差异与肾ANP受体的密度或亲和力差异无关，但当在存在10(-3) M异丁基甲基黄嘌呤或扎普司特（两种不同的环核苷酸磷酸二酯酶（PDE）抑制剂）的情况下测量cGMP积累时，这种差异消失。向肾炎大鼠的一侧肾动脉输注扎普司特可使对容量扩张的利钠反应以及输注侧而非对侧肾脏的UcGMPV增加恢复正常。此外，与正常大鼠相比，肾炎大鼠IMCD细胞匀浆中的cGMP-PDE活性增加（分别为388±32和198±93 pmol/分钟/毫克蛋白，P<0.03）。这些结果表明，在肾损伤的免疫模型中出现了容量扩张性利钠减弱并伴有体外细胞对ANP的抵抗。这种抵抗与ANP释放或与其肾受体结合的改变无关，但被PDE抑制剂抑制且与肾cGMP增加有关。PDE活性，因此提示增强的cGMP-PDE活性可能是体内观察到的对ANP利钠作用抵抗的原因。这种缺陷可能代表了与肾病综合征钠潴留相关的内在钠转运异常。
