Service of Nephrology, University Hospital of Geneva , Geneva , Switzerland.
Department of Cell Physiology and Metabolism, University Medical Center , Geneva , Switzerland.
Am J Physiol Renal Physiol. 2018 May 1;314(5):F763-F772. doi: 10.1152/ajprenal.00200.2017. Epub 2017 Sep 6.
Acute nephron reduction such as after living kidney donation may increase the risk of hypertension. Uninephrectomy induces major hemodynamic changes in the remaining kidney, resulting in rapid increase of single-nephron glomerular filtration rate (GFR) and fluid delivery in the distal nephron. Decreased sodium (Na) fractional reabsorption after the distal tubule has been reported after uninephrectomy in animals preserving volume homeostasis. In the present study, we thought to specifically explore the effect of unilateral nephrectomy on epithelial Na channel (ENaC) subunit expression in mice. We show that γ-ENaC subunit surface expression was specifically downregulated after uninephrectomy, whereas the expression of the aldosterone-sensitive α-ENaC and α-Na-K-ATPase subunits as well as of kidney-specific Na-K-Cl cotransporter isoform and Na-Cl cotransporter were not significantly altered. Because acute nephron reduction induces a rapid increase of single-nephron GFR, resulting in a higher tubular fluid flow, we speculated that local mechanical factors such as fluid shear stress (FSS) were involved in Na reabsorption regulation after uninephrectomy. We further explore such hypothesis in an in vitro model of FSS applied on highly differentiated collecting duct principal cells. We found that FSS specifically downregulates β-ENaC and γ-ENaC subunits at the transcriptional level through an unidentified heat-insensitive paracrine basolateral factor. The primary cilium as a potential mechanosensor was not required. In contrast, protein kinase A and calcium-sensitive cytosolic phospholipase A were involved, but we could not demonstrate a role for cyclooxygenase or epoxygenase metabolites.
急性肾单位减少，如活体肾脏捐献后，可能会增加高血压的风险。单侧肾切除会导致剩余肾脏发生重大血流动力学变化，导致单肾单位肾小球滤过率（GFR）和远端肾单位的液体输送迅速增加。在动物中，单侧肾切除后，据报道在远曲小管后，钠（Na）的分数重吸收减少，以维持容量平衡。在本研究中，我们特别想探讨单侧肾切除对小鼠上皮钠通道（ENaC）亚基表达的影响。我们发现，γ-ENaC 亚基的表面表达在单侧肾切除后特异性地下调，而醛固酮敏感的α-ENaC 和α-Na-K-ATP 酶亚基以及肾脏特异性的 Na-K-Cl 共转运体同工型和 Na-Cl 共转运体的表达没有明显改变。因为急性肾单位减少会导致单肾单位 GFR 的迅速增加，从而导致肾小管液流量增加，我们推测局部机械因素，如流体切应力（FSS），参与了单侧肾切除后的 Na 重吸收调节。我们在高度分化的集合管主细胞的 FSS 体外模型中进一步探讨了这种假说。我们发现，FSS 通过一种未知的不耐热旁分泌基底外侧因子，特异性地下调β-ENaC 和γ-ENaC 亚基的转录水平。初级纤毛作为潜在的机械感受器不是必需的。相反，蛋白激酶 A 和钙敏感的细胞质磷脂酶 A 参与其中，但我们不能证明环氧化酶或环氧化物酶代谢物的作用。
