Genetic Deletion of P2Y2 Receptor Suppresses Lithium‐induced Medullary Collecting Duct Remodeling in Mice

Abstract

Previously we reported that genetic deletion of P2Y2 receptor (R) significantly protects against lithium (Li)-induced nephrogenic diabetes insipidus (NDI) by suppressing polyuria, natriuresis and kaliuresis even on long-term basis (5 months). Li administration also results in collecting duct remodeling, whereby the proportion of H+-ATPase-positive intercalated cells (IC) increase relative to the proportion of AQP2-positive principal cells (PC). Hence, we investigated whether P2Y2-R deletion has a significant effect on Li-induced medullary collecting duct (mCD) remodeling. Li was administered to wild type (WT) and P2Y2-R knockout (KO) mice (both in B6D2 genetic background) embedded in food for either 5 months (40 mmol LiCl/kg chow) or 30 days (40 mmol/kg chow for 7 days followed by 60 mmol LiCl/kg chow), and humanely euthanized. Using confocal immunofluorescence microscopy and double labeling, kidney sections from 4 to 7 mice per group were examined for the percent of cells labeled for AQP2 or H+-ATPase or none. Cell proliferation was assessed by immunolabeling for Ki67. Bar graph below shows the results for collecting duct remodeling. In both series, Li feeding significantly (P < 0.05) decreased the percent of PC and increased IC cells in the WT but not in the KO mice. In both series, Li-treatment resulted in significant (P < 0.05) differences in the PC and IC proportions between WT and KO mice. Furthermore, Li-induced differences in PC/IC ratio in WT mice were more marked in the long-term series. In the high-dose study Li-induced higher percent of double negative (DN) cells in the KO mice, but not in the WT mice. Li treatment caused significant increase in Ki67 labeling in PC and IC cells in WT, but not in KO mice, indicating that proliferation of both cell types contribute to CD remodeling. These results suggest that P2Y2-R plays a significant role in Li-induced conversion of PC to IC cells, and thus shed new light on the cell biology of collecting duct remodeling. Support or Funding Information Department of Veterans Affairs; National Institutes of Health This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.