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Abstract: FR-PO288

The Renal Circadian Clock Is Disrupted in Autosomal Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1101 Genetic Diseases of the Kidneys: Cystic


  • Jamadar, Abeda, University of Kansas Medical Center Department of Internal Medicine, Kansas City, Kansas, United States
  • Douma, Lauren G., University of Florida, Gainesville, Florida, United States
  • Gumz, Michelle L., University of Florida, Gainesville, Florida, United States
  • Rao, Reena, University of Kansas Medical Center Department of Internal Medicine, Kansas City, Kansas, United States

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease. Based on a never-before described observation of unusually high night-time activity in the Pkd1R3277C (RC/RC) mouse model of ADPKD, we examined their circadian rhythms. Circadian rhythms are intrinsic cyclical ~24-hour oscillations in behavior and physiology, which at the molecular level are regulated by circadian clock proteins that regulate gene expression. The circadian clock regulates renal functions, which are disrupted in some kidney diseases. Here we examined the renal circadian rhythms in ADPKD


Circadian oscillation of clock proteins was examined in RC/RC and wild type (WT) mouse kidneys; and in Pkd1 gene knockout mouse renal proximal tubular cells (PT-Pkd1-/-) and inner medullary collecting duct cells (IMCD3-Pkd1-/-) and controls (PT-Pkd1+/- and IMCD3-Pkd1+/+ cells). For real-time visualization of circadian dynamics in ADPKD kidneys, bioluminescence rhythms were measured in kidney tissue explants from RC/RC and WT mice expressing Per2Luciferase gene. Diurnal rhythms of urine output and water intake were also measured in RC/RC and WT mice.


PT-Pkd1-/- and IMCD3-Pkd1-/- cells showed significantly disrupted oscillations of multiple clock genes, including BMAL1, CLOCK, CRY1 and Per2 when compared to control cells which displayed clock gene oscillations at 20-24h intervals. We found significant differences in mRNA levels of multiple clock genes in RC/RC mouse kidneys, compared to WT controls. In particular, both mRNA and protein levelsof Per2 showed significant difference between WT and RC/RC kidneys. While the WT-Per2Luciferasekidney tissue explants showed persistent bioluminescence rhythms, lower-amplitude rhythms with shorter circadian periods were found in RC/RC-Per2Luciferase kidney explants. We also found significant differences in diurnal rhythms of urine output and water intake in RC/RC mice compared to WT mice.


This study shows for the first time that (A) cultured renal tubular epithelial cells are good oscillators, but Pkd1 gene deletion disrupts the circadian clock gene rhythms of tubular epithelial cells, the very cells that form cysts, and (B) circadian rhythms of clock genes as well as renal functions are disrupted in RC/RC mouse kidneys. Renal circadian rhythms are thus disrupted in ADPKD.


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