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.
Highlights
In proximal tubules (PT), flow-modulated salt and water reabsorption is largely responsible for glomerulotubular balance (GTB), namely the constancy of fractional distal Na+ delivery during variations in glomerular filtration rate (GFR) [1, 2]
We observed no morphological changes of the kidneys from the Pkd1, Pkd2, and the Kif3a-KO mice 2 weeks after the induction and observed some dilated kidney tubules after 5 weeks of induction; renal cysts developed from 8 weeks of induction in Pkd1 and Pkd2 KO mice [20]
The results indicated that a minimum number of 720 mice would be needed for each group to obtain significant difference on BUN, kidney body weight ratio, and cystic index between control and treated groups in Pkd1-KO mice, as we demonstrated in Pkd2-KO mice
Summary
In proximal tubules (PT), flow-modulated salt and water reabsorption is largely responsible for glomerulotubular balance (GTB), namely the constancy of fractional distal Na+ delivery during variations in glomerular filtration rate (GFR) [1, 2]. Cell volume integrity is preserved during flow-dependent transport, since luminal FSS modulates Na+/K+-ATPase translocation to the peritubular membrane [6]. An important parameter of FSS-dependent Na+ reabsorption is the flow sensitivity, defined as the fractional change in transport relative to the fractional change in FSS. With respect to the important regulators of PT transport, angiotensin acts to increase absolute PT Na+ and HCO3– reabsorption with little perturbation of their flow sensitivity [7]. Dopamine does little to perturb baseline fluxes but markedly blunts flow sensitivity. In these experiments, the dopamine receptor 1 (DA1) antagonist SCH23390 increased flow sensitivity of Na+ and HCO3– reabsorption to supernormal values [8]
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