Effect of renal tubule-specific knockdown of the Na+/H+ exchanger NHE3 in Akita diabetic mice
Effect of renal tubule-specific knockdown of the Na+/H+ exchanger NHE3 in Akita diabetic mice
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DOI：
10.1152/ajprenal.00497.2018
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发表时间：
2019-08-01
影响因子：
4.2
通讯作者：
Vallon, Volker
中科院分区：
文献类型：
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作者：
Onishi, Akira;Fu, Yiling;Vallon, Volker
Na+/H+交换异构体3 （NHE3）参与早期近端小管Na+/碳酸氢盐的重吸收和铵的分泌。为了确定其在糖尿病肾脏中的作用，1型糖尿病秋田小鼠管状NHE3敲低[Pax8-Cre；nhe3敲除（KO）小鼠]。NHE3-KO小鼠的尿液pH值更高，碳酸氢钠含量更多，与近端小管中铵、碳酸氢盐和葡萄糖（磷酸烯醇丙酮酸羧激酶）的产生以及远端小管中H+、氨分泌和糖酵解相关的基因mRNA表达的补偿性增加。与野生型小鼠相比，非糖尿病和糖尿病NHE3-KO小鼠的血液pH值和碳酸氢盐未受影响，但与肾脏促炎标志物上调有关。NHE3-KO小鼠肾磷酸烯醇丙酮酸羧激酶表达升高与Na+-葡萄糖共转运蛋白（SGLT）2和SGLT1表达升高相关。表明钠离子和葡萄糖的再吸收发生了向下的管状移动。NHE3-KO与较小的肾脏重量和独立于糖尿病的肾小球滤过率（GFR）相关，并预防糖尿病相关的蛋白尿。然而，NHE3-KO并没有减轻高血糖或防止糖尿病增加肾脏重量和GFR。与野生型小鼠相比，糖尿病NHE3-KO小鼠尽管SGLT2表达较低且血糖较高，但较高的肾糖异生可能解释了类似的高血糖；更强的SGLT1参与可能影响肾脏重量和GFR反应。人类慢性肾病与支链氨基酸代谢物尿排泄减少和三羧酸循环有关，这种模式在糖尿病野生型小鼠中被模仿。这种模式在非糖尿病的NHE3-KO小鼠中被逆转，可能反映了支链氨基酸用于氨生成和三羧酸循环的上调，以支持近端小管中氨、碳酸氢盐和葡萄糖的形成。然而，NHE3-KO并不能阻止糖尿病引起的尿中这些代谢物的下调。
Na+/H+ exchanger isoform 3 (NHE3) contributes to Na+/bicarbonate reabsorption and ammonium secretion in early proximal tubules. To determine its role in the diabetic kidney, type 1 diabetic Akita mice with tubular NHE3 knockdown [Pax8-Cre; NHE3-knockout (KO) mice] were generated. NHE3-KO mice had higher urine pH, more bicarbonaturia, and compensating increases in renal mRNA expression for genes associated with generation of ammonium, bicarbonate, and glucose (phosphoenolpyruvate carboxykinase) in proximal tubules and H+ and ammonia secretion and glycolysis in distal tubules. This left blood pH and bicarbonate unaffected in nondiabetic and diabetic NHE3-KO versus wild-type mice but was associated with renal upregulation of proinflammatory markers. Higher renal phosphoenolpyruvate carboxykinase expression in NHE3-KO mice was associated with lower Na+-glucose cotransporter (SGLT)2 and higher SGLT1 expression. indicating a downward tubular shift in Na+ and glucose reabsorption. NHE3-KO was associated with lesser kidney weight and glomerular filtration rate (GFR) independent of diabetes and prevented diabetes-associated albuminuria. NHE3-KO, however, did not attenuate hyperglycemia or prevent diabetes from increasing kidney weight and GFR. Higher renal gluconeogenesis may explain similar hyperglycemia despite lower SGLT2 expression and higher glucosuria in diabetic NHE3-KO versus wild-type mice; stronger SGLT1 engagement could have affected kidney weight and GFR responses. Chronic kidney disease in humans is associated with reduced urinary excretion of metabolites of branched-chain amino acids and the tricarboxylic acid cycle, a pattern mimicked in diabetic wild-type mice. This pattern was reversed in nondiabetic NHE3-KO mice, possibly reflecting branched-chain amino acids use for ammoniagenesis and tricarboxylic acid cycle upregulation to support formation of ammonia, bicarbonate, and glucose in proximal tubule. NHE3-KO, however, did not prevent the diabetes-induced urinary downregulation in these metabolites.