Department of Cellular and Molecular Physiology, Yale School of Medicine University, 333 Cedar Street, P.O. Box 208026, New Haven, CT, 06520-8026, USA.
Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY, USA.
Pflugers Arch. 2021 Nov;473(11):1749-1760. doi: 10.1007/s00424-021-02611-5. Epub 2021 Aug 29.
We compared the regulation of the NaCl cotransporter (NCC) in adaptation to a low-K (LK) diet in male and female mice. We measured hydrochlorothiazide (HCTZ)-induced changes in urine volume (UV), glomerular filtration rate (GFR), absolute (ENa, EK), and fractional (FENa, FEK) excretion in male and female mice on control-K (CK, 1% KCl) and LK (0.1% KCl) diets for 7 days. With CK, NCC-dependent ENa and FENa were larger in females than males as observed previously. However, with LK, HCTZ-induced ENa and FENa increased in males but not in females, abolishing the sex differences in NCC function as observed in CK group. Despite large diuretic and natriuretic responses to HCTZ, EK was only slightly increased in response to the drug when animals were on LK. This suggests that the K-secretory apparatus in the distal nephron is strongly suppressed under these conditions. We also examined LK-induced changes in Na transport protein expression by Western blotting. Under CK conditions females expressed more NCC protein, as previously reported. LK doubled both total (tNCC) and phosphorylated NCC (pNCC) abundance in males but had more modest effects in females. The larger effect in males abolished the sex-dependence of NCC expression, consistent with the measurements of function by renal clearance. LK intake did not change NHE3, NHE2, or NKCC2 expression, but reduced the amount of the cleaved (presumably active) form of γENaC. LK reduced plasma K to lower levels in females than males. These results indicated that males had a stronger NCC-mediated adaptation to LK intake than females.
我们比较了 NaCl 协同转运蛋白（NCC）在适应低 K（LK）饮食中的调节作用，在雄性和雌性小鼠中测量了氢氯噻嗪（HCTZ）诱导的尿量（UV）、肾小球滤过率（GFR）、绝对（ENa、EK）和分数（FENa、FEK）排泄的变化，雄性和雌性小鼠分别在对照 K（CK，1% KCl）和 LK（0.1% KCl）饮食中 7 天。在 CK 时，如先前观察到的，NCC 依赖性 ENa 和 FENa 在雌性中大于雄性。然而，在 LK 时，HCTZ 诱导的 ENa 和 FENa 在雄性中增加，但在雌性中没有增加，从而消除了在 CK 组中观察到的 NCC 功能的性别差异。尽管 HCTZ 引起了大量的利尿和排钠反应，但当动物处于 LK 时，EK 仅略微增加对药物的反应。这表明在这些条件下，远端肾单位的 K 分泌装置受到强烈抑制。我们还通过 Western 印迹法检查了 LK 诱导的 Na 转运蛋白表达变化。在 CK 条件下，如先前报道的，雌性表达更多的 NCC 蛋白。LK 在雄性中使总 NCC（tNCC）和磷酸化 NCC（pNCC）的丰度增加了一倍，但在雌性中影响较小。雄性中的更大影响消除了 NCC 表达的性别依赖性，与肾清除率测量的功能一致。LK 摄入不改变 NHE3、NHE2 或 NKCC2 的表达，但减少了切割（推测为活性）形式的 γENaC 的量。LK 使雌性的血浆 K 降低到比雄性更低的水平。这些结果表明，雄性比雌性具有更强的 NCC 介导的适应 LK 摄入的能力。
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