The study on molecular biological mechanisms and therapy of sodiam and acid disturbance in renal failure

慢性肾功能衰竭患者尿中钠和酸的排泄减少。肾脏中的几种离子转运体参与钠和酸的排泄。我们重点研究了分泌型Na-K-2Cl共转运蛋白（NKCC1）。为了了解NKCC1在体液平衡调节中的作用，我们研究了NKCC1在小鼠和大鼠肾细胞中的分布。NKCC1 mRNA在小鼠髓内集管（IMCD）和大鼠髓外集管（OMCD）中表达最丰富。NH4C1处理和2 d脱水诱导的慢性代谢性酸中毒导致OMCD收集管中NKCC1 mRNA表达和NKCC1蛋白表达显著升高。接下来，为了研究脱水上调NKCC1 mRNA表达的机制，我们研究了高渗和抗利尿激素（AVP）对其表达的影响。高渗透压和AVP增加了OMCD中NKCC1 mRNA的表达。这些结果表明，AVP直接或间接通过增加髓质渗透压调节NKCC1的表达。由于慢性肾衰竭患者V2抗利尿激素受体下调，AVP在肾衰竭患者钠和酸排泄中起重要作用。

Patients with chronic renal failure showed decreased urinary excretion of sodium and acid. Several ion transporters in the kidney participate in sodium and acid excretion. We focused on secretory type Na-K-2Cl cotransporter (NKCC1). To know the role of NKCC1 in the regulation of body fluid homeostasis, we investigated the distribution of NKCC1 along the nephron in mouse and rat. NKCC1 mRNA expression was most abundant in inner medullary collecting ducts (IMCD) in mouse and outer medullary collecting ducts (OMCD) in rat. Chronic metabolic acidosis induced by the administration of NH4C1 and two-days dehydration caused a significant increases of NKCC1 mRNA expression in collecting ducts and NKCC1 protein expression in OMCD. Next, to examine the mechanisms of the up-regulation of NKCC1 mRNA expression by dehydration, the effects of hyperosmolality and vasopressin (AVP) on its expression were studied. Hyperosmolality and AVP increased NKCC1 mRNA expression in OMCD. These results show that AVP, directly or indirectly through the increase in medullary osmolality, regulates NKCC1 expression. Since V2 vasopressin receptors were downregulated in chronic renal failure, AVP plays an important role in sodium and acid excretion in patients with renal failure.