Deletion of the Circadian Clock Gene Bmal1 in Renal Collecting Ducts Leads to Rapid Cyst Growth in Autosomal Dominant Polycystic Kidney Disease
- Investigations in Polycystic and Tubulointerstitial Kidney Diseases
November 02, 2023 | Location: Room 105, Pennsylvania Convention Center
Abstract Time: 05:33 PM - 05:42 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Cystic
- Jamadar, Abeda, University of Kansas Medical Center Department of Internal Medicine, Kansas City, Kansas, United States
- Varghese, Meekha Mary, University of Kansas Medical Center Department of Internal Medicine, Kansas City, Kansas, 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 an inherited kidney disease characterized by progressive cyst growth from the nephrons that can lead to loss of renal function and end stage renal disease. Here we examined if disruption of the circadian clock can alter ADPKD progression. Circadian rhythms are intrinsic, cyclical ~24-hour oscillations in behavior and physiology that coordinate biological processes with the time of day. In mammals, circadian rhythms are regulated by cell-autonomous circadian clocks. BMAL1 is a transcription activator, and a core component of the circadian clock, which plays an important role in physiological rhythms including the cell cycle, metabolism, and inflammation.
To determine the effect of Bmal1 gene deletion in ADPKD kidneys, we used the Pkd1RC/RC mouse, a Pkd1 gene hypomorph mouse model of ADPKD. Pkd1RC/RC;Bmal1f/f;Pkhd1cre mice (RC/RC-Bmal1KO) in which Bmal1 (Arntl1 gene) was specifically deleted in the renal collecting ducts and connecting tubules was generated on pure C57BL6/J background and compared with wild type (WT) and Bmal1f/f;Pkhd1cre mice (RC/RC-Bmal1KO). All the mice were sacrificed at 8 months of age at noon time and kidneys were analyzed
We found that the disease progressed rapidly in RC/RC-Bmal1KO mouse kidneys. At 8 months, RC/RC-Bmal1KO littermates showed significantly larger kidneys with significantly higher kidney/body weight ratio and cyst area as compared to RC/RC kidneys. In addition, we found that RC/RC-Bmal1KO kidneys had increased cell proliferation and apoptosis as indicated by higher KI-67 and TUNEL staining, respectively. Immunoblot analysis showed significantly increased expression of pro-proliferative factors in RC/RC-Bmal1KO kidneys compared to RC/RC kidneys. Bulk RNA seq analysis indicated significantly reduced fatty acid metabolism in RC/RC mice as compared to WT mice, which was further reduced in RC/RC-Bmal1KO mice.
These results show for the first time that disruption of the renal circadian clock is a trigger for early and accelerated disease progression in ADPKD.
- NIDDK Support