Kidney Week

Abstract: FR-PO288

The Renal Circadian Clock Is Disrupted in Autosomal Polycystic Kidney Disease

Session Information

• Genetic Diseases of the Kidneys: Cystic - II
  November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1101 Genetic Diseases of the Kidneys: Cystic

Authors

• Jamadar, Abeda, University of Kansas Medical Center Department of Internal Medicine, Kansas City, Kansas, United States

Abeda Jamadar,

• Douma, Lauren G., University of Florida, Gainesville, Florida, United States

Lauren G. Douma,

• Gumz, Michelle L., University of Florida, Gainesville, Florida, United States

Michelle L. Gumz,

• Rao, Reena, University of Kansas Medical Center Department of Internal Medicine, Kansas City, Kansas, United States

Reena Rao,

Background

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 Pkd1^R3277C (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

Methods

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 Per2^Luciferase gene. Diurnal rhythms of urine output and water intake were also measured in RC/RC and WT mice.

Results

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-Per2^Luciferasekidney tissue explants showed persistent bioluminescence rhythms, lower-amplitude rhythms with shorter circadian periods were found in RC/RC-Per2^Luciferase kidney explants. We also found significant differences in diurnal rhythms of urine output and water intake in RC/RC mice compared to WT mice.

Conclusion

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.

Funding

• NIDDK Support