Abstract: TH-PO593

Lack of Alpha-Intercalated Cells Links Autosomal Dominant Polycystic Kidney Disease to Urinary Tract Infection in Mice and Humans

Session Information

Category: Developmental Biology and Inherited Kidney Diseases

  • 402 Stem Cells


  • Gao, Chao, Albany medical college, Albany, New York, United States
  • Zhang, Long, Albany medical college, Albany, New York, United States
  • Chen, Lihe, NIH, Bethesda, Maryland, United States
  • Zhang, Ye, AMC, Albany, New York, United States
  • Chen, Enuo, Albany Medical College, Albany, New York, United States
  • Wallace, Darren P., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Zhou, Qiaoling, Xiangya Hospital, Changsha, China
  • Higgins, Paul J., Albany Medical College, Albany, New York, United States
  • Zhang, Wenzheng, Albany Medical College, Albany, New York, United States

Urinary tract infection (UTI) is a common feature of autosomal dominant polycystic kidney disease (ADPKD) with ~30-50% of ADPKD patients having at least one UTI during their lifetime. However, the underlying cellular and molecular mechanisms linking ADPKD to UTI remain unaddressed.


Hence, Pkd2f/f Aqp2Cre mice were generated to disrupt Pkd2 in Aqp2+ progenitor cells, which give rise to all known cell types of the connecting tubule/collecting duct (CNT/CD).


Pkd2f/f Aqp2Cre mice developed severe PKD and died by P17. Double and triple immunofluorescence (IF) staining for various segment- and/or cell-specific markers were conducted. At least 1000 CNT/CD cells from 3 Pkd2f/f Aqp2Cre and 3 WT mice for each IF combination were categorized and counted based on the marker expression. Using Aqp2, V-ATPase B1B2 and AE1 as markers for principal cells (PC), intercalated cells (IC) and a-IC, respectively, we found that Pkd2f/f Aqp2Cre mice had a reduced IC/PC ratio from 37.61±1.23% in WT to 7.45±1.08% and completely lost a-IC at P17. Neutralized urine from Pkd2f/f Aqp2Cre mice is significantly less inhibitory for bacterial growth than that from WT mice. In P6 Pkd2f/f Aqp2Cre mice, cysts began to be detectable with occasional presence of a-IC. TUNEL assay showed that IC, particular a-IC, were more apoptotic than PC. We conducted the same IF with kidneys from ADPKD patients (n=27) and minimal change disease patients (MCD) as normal control (n=5). While all PC and IC markers were readily detectable in each of MCD samples, cysts containing AQP2+ cells were found only in 13 ADPKD samples. Among these 13 ADPKD samples, we counted >4000 CNT/CD cells and found that ADPKD diminished the IC/PC ratio from 26.07±6.19% in MCD to 10.12±6.53%. None of the ADPKD kidneys had AE1+ cells in Aqp2+ labeled cystic structure. Seldom AE1+ cells were observed in apparently normal CNT/CD of some ADPKD kidneys.


Our data suggest that Pkd2 deletion in Aqp2+ progenitor cells is sufficient for PKD development, and a-IC are selectively depleted with the disease development in both mice and human. The lack of a-IC to acidify urine and secret neutrophil gelatinase-associated lipocalin (NGAL) that chelates siderophore-containing iron may link ADPKD to UTI.


  • NIDDK Support