Restoration of proximal tubule flow-activated transport prevents cyst growth in polycystic kidney disease. Academic Article uri icon

Overview

abstract

  • Flow-activated Na+ and HCO3- transport in kidney proximal tubules (PT) underlies relatively constant fractional reabsorption during changes in glomerular filtration rate (GFR) or glomerulotubular balance (GTB). In view of hypothesized connections of epithelial cilia to flow sensing, we examined flow-activated transport in 3 polycystic kidney disease-related mouse models based on inducible conditional KO of Pkd1, Pkd2, and Kif3a. PTs were harvested from mice after gene inactivation but prior to cyst formation, and flow-mediated PT transport was measured. We confirm that higher flow increased both Na+ and HCO3- absorption in control mice, and we observed that this flow effect was preserved in PTs of Pkd1-/- and Kif3a-/-mice. However, flow activation was absent in Pkd2+/- and Pkd2-/- PT. In heterozygous (Pkd2+/-) mice, a dopamine receptor 1 (DA1) antagonist (SCH23390) restored transport flow sensitivity. When given chronically, this same antagonist reduced renal cyst formation in Pkd2-/-, as evidenced by reduced kidney weight, BUN, and the cystic index, when compared with untreated mice. In contrast, SCH23390 did not prevent cyst formation in Pkd1-/- mice. These results indicate that Pkd2 is necessary for normal GTB and that restoration of flow-activated transport by DA1 antagonist can slow renal cyst formation in Pkd2-/- mice.

publication date

  • May 24, 2021

Research

keywords

  • Kidney Tubules, Proximal
  • Polycystic Kidney Diseases

Identity

PubMed Central ID

  • PMC8262298

Scopus Document Identifier

  • 85106526184

Digital Object Identifier (DOI)

  • 10.1172/jci.insight.146041

PubMed ID

  • 33886508

Additional Document Info

volume

  • 6

issue

  • 10