Attenuation of lithium-induced natriuresis and kaliuresis in P2Y(2) receptor knockout mice

作者：Zhang Yue; Li Lijun; Kohan Donald E; Ecelbarger Carolyn M; Kishore Bellamkonda K^*

来源：American Journal of Physiology - Renal Fluid and Electrolyte Physiology, 2013, 305(3): F407-F416.

DOI：10.1152/ajprenal.00464.2012

• vasopressin
• aldosterone
• sodium transporters
• epithelial sodium channel
• potassium channels
• ATP
• nephrogenic diabetes insipidus

Whole body knockout (KO) of the P2Y(2) receptor (P2Y(2)R) results in enhanced vasopressin V2 receptor activity and increased renal Na+ conservation. We hypothesized that P2Y(2)R KO mice would be less sensitive to lithium-induced natriuresis and kaliuresis due to attenuated downregulation of one or more of the major renal Na+ or K+ transporter/channel proteins. KO and wild-type (WT) mice were fed a control or lithium-added diet (40 mmol/kg food) for 14 days. Lithium-induced natriuresis and kaliuresis were significantly (similar to 25%) attenuated in KO mice. The subunits of the epithelial Na+ channel (ENaC) were variably affected by lithium and genotype, but, overall, medullary levels were decreased substantially by lithium (15-60%) in both genotypes. In contrast, cortical, beta-, and gamma-ENaC were increased by lithium (similar to 50%), but only in WT mice. Moreover, an assessment of ENaC activity by benzamil sensitivity suggested that lithium increased ENaC activity in WT mice but in not KO mice. In contrast, medullary levels of Na+-K+-2Cl(-) cotransporter 2 and cortical levels of the renal outer medullary K+ channel were not downregulated by lithium and were significantly (15-76%) higher in KO mice under both dietary conditions. In addition, under control conditions, tissue osmolality of the inner medulla as well as furosemide sensitivity were significantly higher in KO mice versus WT mice. Therefore, we suggest that increased expression of these proteins, particularly in the control state, reduces Na+ delivery to the distal nephron and provides a buffer to attenuate collecting duct-mediated natriuresis and kaliuresis. Additional studies are warranted to explore the potential therapeutic benefits of purinergic antagonism.

• 出版日期2013-8