Division of Nephrology and Transplantation, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Am J Physiol Renal Physiol. 2021 Apr 1;320(4):F654-F668. doi: 10.1152/ajprenal.00603.2020. Epub 2021 Feb 15.
Chronic kidney disease contributes to hypertension, but the mechanisms are incompletely understood. To address this, we applied the 5/6th nephrectomy rat model to characterize hypertension and the response to dietary salt and renin-angiotensin inhibition. 5/6th nephrectomy caused low-renin, salt-sensitive hypertension with hyperkalemia and unsuppressed aldosterone. Compared with sham rats, 5/6th nephrectomized rats had lower Na/H exchanger isoform 3, Na-K-2Cl cotransporter, Na-Cl cotransporter, α-epithelial Na channel (ENaC), and Kir4.1 levels but higher serum and glucocorticoid-regulated kinase 1, prostasin, γ-ENaC, and Kir5.1 levels. These differences correlated with plasma renin, aldosterone, and/or K. On a normal-salt diet, adrenalectomy (0 ± 9 mmHg) and spironolactone (-11 ± 10 mmHg) prevented a progressive rise in blood pressure (10 ± 8 mmHg), and this was enhanced in combination with losartan (-41 ± 12 and -43 ± 9 mmHg). A high-salt diet caused skin Na and water accumulation and aggravated hypertension that could only be attenuated by spironolactone (-16 ± 7 mmHg) and in which the additive effect of losartan was lost. Spironolactone also increased natriuresis, reduced skin water accumulation, and restored vasorelaxation. In summary, in the 5/6th nephrectomy rat chronic kidney disease model, salt-sensitive hypertension develops with a selective increase in γ-ENaC and despite appropriate transporter adaptations to low renin and hyperkalemia. With a normal-salt diet, hypertension in 5/6th nephrectomy depends on angiotensin II and aldosterone, whereas a high-salt diet causes more severe hypertension mediated through the mineralocorticoid receptor. Chronic kidney disease (CKD) causes salt-sensitive hypertension, but the interactions between dietary salt and the renin-angiotensin system are incompletely understood. In rats with CKD on a normal-salt diet targeting aldosterone, the mineralocorticoid receptor (MR) and especially angiotensin II reduced blood pressure. On a high-salt diet, however, only MR blockade attenuated hypertension. These results reiterate the importance of dietary salt restriction to maintain renin-angiotensin system inhibitor efficacy and specify the MR as a target in CKD.
慢性肾脏病会导致高血压，但其中的机制尚不完全清楚。为了解决这个问题，我们应用 5/6 肾切除大鼠模型来描述高血压以及对饮食盐和肾素-血管紧张素抑制的反应。5/6 肾切除导致低肾素、盐敏感型高血压伴高钾血症和醛固酮不受抑制。与假手术大鼠相比，5/6 肾切除大鼠的 Na/H 交换体 3、Na-K-2Cl 共转运体、Na-Cl 共转运体、α-上皮 Na 通道（ENaC）和 Kir4.1 水平较低，但血清和糖皮质激素调节激酶 1、前列腺素、γ-ENaC 和 Kir5.1 水平较高。这些差异与血浆肾素、醛固酮和/或 K 相关。在正常盐饮食下，肾上腺切除术（0±9mmHg）和螺内酯（-11±10mmHg）可防止血压的持续升高（10±8mmHg），与氯沙坦联合使用可增强这种效果（-41±12mmHg 和-43±9mmHg）。高盐饮食导致皮肤钠和水积聚，并加重高血压，而螺内酯（-16±7mmHg）可减轻这种情况，且氯沙坦的相加作用丧失。螺内酯还可增加排钠量，减少皮肤水分积聚，并恢复血管舒张。总之，在 5/6 肾切除大鼠慢性肾脏病模型中，尽管存在对低肾素和高钾血症的适当转运体适应，但仍会发生盐敏感型高血压，并伴有γ-ENaC 的选择性增加。在正常盐饮食下，5/6 肾切除引起的高血压依赖于血管紧张素 II 和醛固酮，而高盐饮食引起的高血压则通过盐皮质激素受体介导更为严重。慢性肾脏病（CKD）导致盐敏感型高血压，但饮食盐与肾素-血管紧张素系统之间的相互作用尚不完全清楚。在正常盐饮食下针对醛固酮的 CKD 大鼠中，盐皮质激素受体（MR），特别是血管紧张素 II，可降低血压。然而，在高盐饮食中，只有 MR 阻断才能减轻高血压。这些结果再次强调了限制饮食盐的重要性，以维持肾素-血管紧张素系统抑制剂的疗效，并明确了 MR 是 CKD 的治疗靶点。
