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Abstract: PO0694

Dysfunction of the Renal Tubular Circadian Clock Leads to Enhanced Renal Gluconeogenesis and Exacerbated Hyperglycemia in Diabetes

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Ansermet, Camille, Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
  • Centeno, Gabriel, Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
  • Bignon, Yohan, Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
  • Garcia, Andy, Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
  • Pradervand, Sylvain, Genomic Technologies Facility, University of Lausanne, Lausanne, Switzerland
  • Firsov, Dmitri, Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
Background

The circadian rhythms define all biological process cycling with a periodicity of about 24 hours. They are believed to be an evolutionary adaptation that allows biological functions to anticipate variations of environmental conditions imposed by Earth rotation. These rhythms are driven by the circadian clock, a molecular system of interconnecting loops present in virtually each cell of the body. Disturbance of the circadian rhythms or its misalignment with external environment is a risk factor for development of numerous diseases, such as depression, obesity, diabetes or cancers. However, the pathophysiological role of intrinsic renal circadian clocks in the diabetic kidney remains unknown.

Methods

To address this question, we used mice with streptozotocin-induced type I diabetes, and carrying Bmal1 deletion either in the podocytes (pcKO mice) or in whole renal tubular cells (tcKO mice).

Results

Although diabetic pcKO mice did not show any additional alterations compared to diabetic Control mice, diabetic tcKO mice showed exacerbated hyperglycemia, increased fractional excretion of glucose, enhanced polyuria and a more severe renal hypertrophy compared to diabetic Control mice. Interestingly, renal gluconeogenic pathway was enhanced in diabetic tcKO mice, as demonstrated by increased protein and mRNA expression levels of key enzymes. Moreover, deep sequencing transcriptome and functional analysis of diabetic cKOt mice showed alterations in several mechanisms affecting the gluconeogenic pathway.

Conclusion

Altogether, our data demonstrate that disturbance of renal tubular circadian clock enhances gluconeogenesis in proximal tubule, leading to the aggravation of the hyperglycemia of diabetic mice. These results highlight importance of circadian behaviour in diabetic patients.

Funding

  • Other NIH Support