Restoration of proximal tubule flow–activated transport prevents cyst growth in polycystic kidney disease
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...
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2021-05-01
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| Series: | JCI Insight |
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| Online Access: | https://doi.org/10.1172/jci.insight.146041 |
| _version_ | 1828808056862932992 |
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| author | Zhaopeng Du Xin Tian Ming Ma Stefan Somlo Alan M. Weinstein Tong Wang |
| author_facet | Zhaopeng Du Xin Tian Ming Ma Stefan Somlo Alan M. Weinstein Tong Wang |
| author_sort | Zhaopeng Du |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T08:33:58Z |
| format | Article |
| id | doaj.art-5ea40e9c0aa04db388b3ff6be8d768ec |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-12-12T08:33:58Z |
| publishDate | 2021-05-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-5ea40e9c0aa04db388b3ff6be8d768ec2022-12-22T00:30:59ZengAmerican Society for Clinical investigationJCI Insight2379-37082021-05-01610Restoration of proximal tubule flow–activated transport prevents cyst growth in polycystic kidney diseaseZhaopeng DuXin TianMing MaStefan SomloAlan M. WeinsteinTong WangFlow-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.https://doi.org/10.1172/jci.insight.146041Nephrology |
| spellingShingle | Zhaopeng Du Xin Tian Ming Ma Stefan Somlo Alan M. Weinstein Tong Wang Restoration of proximal tubule flow–activated transport prevents cyst growth in polycystic kidney disease JCI Insight Nephrology |
| title | Restoration of proximal tubule flow–activated transport prevents cyst growth in polycystic kidney disease |
| title_full | Restoration of proximal tubule flow–activated transport prevents cyst growth in polycystic kidney disease |
| title_fullStr | Restoration of proximal tubule flow–activated transport prevents cyst growth in polycystic kidney disease |
| title_full_unstemmed | Restoration of proximal tubule flow–activated transport prevents cyst growth in polycystic kidney disease |
| title_short | Restoration of proximal tubule flow–activated transport prevents cyst growth in polycystic kidney disease |
| title_sort | restoration of proximal tubule flow activated transport prevents cyst growth in polycystic kidney disease |
| topic | Nephrology |
| url | https://doi.org/10.1172/jci.insight.146041 |
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