Kir4.2 mediates proximal potassium effects on glutaminase activity and kidney injury.
Kir4.2 mediates proximal potassium effects on glutaminase activity and kidney injury.
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DOI：
10.1016/j.celrep.2022.111840
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发表时间：
2022-12-20
期刊：
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
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钾 (K+) 消耗不足与死亡率增加和心血管结局不佳相关。先前已描述过钾对血压的影响；然而，低 K+ 是否独立影响肾脏疾病的进展仍不清楚。在这里，我们证明膳食 K+ 缺乏会导致直接肾损伤。效果取决于血液 K+ 的减少，并且具有肾脏特异性。为了响应 K+ 减少，通道 Kir4.2 介导改变近端小管 (PT) 基底外侧 K+ 通量，导致细胞内酸中毒以及谷氨酰胺酶和氨生成途径的激活。删除 Kir4.2 或谷氨酰胺酶可防止低 K+ 损伤。在醛固酮增多症模型中，K+ 减少还会介导损伤和纤维化。这些结果表明，PT 上皮与远端肾单位一样，对 K+ 敏感，血液 K+ 减少会导致直接 PT 损伤。 Kir4.2 和谷氨酰胺酶是这一损伤过程的重要介质，我们确定了它们未来治疗慢性肾病的潜力。特克等人。证明膳食 K+ 缺乏会导致肾脏特异性损伤和炎症。作用由近端小管基底外侧 K+ 通道 Kir4.2 介导，该通道可响应血液 K+ 水平降低而促进氨生成。删除该通道或谷氨酰胺酶可以保护动物免受低钾介导的肾损伤。
Inadequate potassium (K+) consumption correlates with increased mortality and poor cardiovascular outcomes. Potassium effects on blood pressure have been described previously; however, whether or not low K+ independently affects kidney disease progression remains unclear. Here, we demonstrate that dietary K+ deficiency causes direct kidney injury. Effects depend on reduced blood K+ and are kidney specific. In response to reduced K+, the channel Kir4.2 mediates altered proximal tubule (PT) basolateral K+ flux, causing intracellular acidosis and activation of the enzyme glutaminase and the ammoniagenesis pathway. Deletion of either Kir4.2 or glutaminase protects from low-K+ injury. Reduced K+ also mediates injury and fibrosis in a model of aldosteronism. These results demonstrate that the PT epithelium, like the distal nephron, is K+ sensitive, with reduced blood K+ causing direct PT injury. Kir4.2 and glutaminase are essential mediators of this injury process, and we identify their potential for future targeting in the treatment of chronic kidney disease. Terker et al. demonstrate that dietary K+ deficiency causes kidney-specific injury and inflammation. Effects are mediated by the proximal tubule basolateral K+ channel Kir4.2, which promotes ammoniagenesis in response to reduced blood K+ levels. Deletion of this channel or the enzyme glutaminase protect animals from low-K+-mediated kidney injury.
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影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
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DOI：
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影响因子：
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通讯作者：
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影响因子：
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