The circadian clock is disrupted in mice with adenine-induced tubulointerstitial nephropathy

Hiroaki Motohashi, Yu Tahara, Daniel S. Whittaker, Huei Bin Wang, Takahiro Yamaji, Hiromichi Wakui, Atsushi Haraguchi, Mayu Yamazaki, Hiroki Miyakawa, Koki Hama, Hiroyuki Sasaki, Tomoko Sakai, Rina Hirooka, Kengo Takahashi, Miku Takizawa, Saneyuki Makino, Shinya Aoyama, Christopher S. Colwell, Shigenobu Shibata

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Abstract

Chronic Kidney Disease (CKD) is increasing in incidence and has become a worldwide health problem. Sleep disorders are prevalent in patients with CKD raising the possibility that these patients have a disorganized circadian timing system. Here, we examined the effect of adenine-induced tubulointerstitial nephropathy on the circadian system in mice. Compared to controls, adenine-treated mice showed serum biochemistry evidence of CKD as well as increased kidney expression of inflammation and fibrosis markers. Mice with CKD exhibited fragmented sleep behavior and locomotor activity, with lower degrees of cage activity compared to mice without CKD. On a molecular level, mice with CKD exhibited low amplitude rhythms in their central circadian clock as measured by bioluminescence in slices of the suprachiasmatic nucleus of PERIOD 2::LUCIFERASE mice. Whole animal imaging indicated that adenine treated mice also exhibited dampened oscillations in intact kidney, liver, and submandibular gland. Consistently, dampened circadian oscillations were observed in several circadian clock genes and clock-controlled genes in the kidney of the mice with CKD. Finally, mice with a genetically disrupted circadian clock (Clock mutants) were treated with adenine and compared to wild type control mice. The treatment evoked worse kidney damage as indicated by higher deposition of gelatinases (matrix metalloproteinase-2 and 9) and adenine metabolites in the kidney. Adenine also caused non-dipping hypertension and lower heart rate. Thus, our data indicate that central and peripheral circadian clocks are disrupted in the adenine-treated mice, and suggest that the disruption of the circadian clock accelerates CKD progression.

Original languageEnglish
Pages (from-to)728-740
Number of pages13
JournalKidney International
Volume97
Issue number4
DOIs
Publication statusPublished - 2020 Apr

Keywords

  • Clock
  • Per2
  • adenine
  • chronic kidney disease
  • circadian clock
  • creatinine
  • fibrosis
  • kidney
  • renal function

ASJC Scopus subject areas

  • Nephrology

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  • Cite this

    Motohashi, H., Tahara, Y., Whittaker, D. S., Wang, H. B., Yamaji, T., Wakui, H., Haraguchi, A., Yamazaki, M., Miyakawa, H., Hama, K., Sasaki, H., Sakai, T., Hirooka, R., Takahashi, K., Takizawa, M., Makino, S., Aoyama, S., Colwell, C. S., & Shibata, S. (2020). The circadian clock is disrupted in mice with adenine-induced tubulointerstitial nephropathy. Kidney International, 97(4), 728-740. https://doi.org/10.1016/j.kint.2019.09.032