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Abstract: TH-PO744

Disrupting Circadian Control of Autophagy Induces Podocyte Injury and Proteinuria

Session Information

Category: Glomerular Diseases

  • 1403 Podocyte Biology

Authors

  • Wang, Lulu, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
  • Tian, Han, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
  • Yang, Junwei, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
  • Jiang, Lei, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
Background

Diabetic kidney disease (DKD) is the leading cause of end-stage-renal disease. The decrease in podocyte number or density is associated with DKD progression. Currently, there is a lack of effective methods of protecting podocytes or improving damage. The circadian clock exists with a wide range of biological process and controls numerous aspects of physiology to adapt the daily environmental changes caused by Earth's rotation. The renal clock plays an important role in maintaining tubular function, but its effect on podocytes remains unclear.

Methods

Adult C57BL/6J mice and podocyte specific Clock knockout mice (podocyte-Clock-/-) were used to construct the type II diabetes model in vivo. Primary podocytes were cultured in 30mM high glucose. Chromatin immunoprecipitation (CHIP) qPCR analysis and dual-luciferase reporter gene assay were used to elaborate association between Clock and autophagy.

Results

The rhythmic oscillations of Clock were disappeared in high glucose treated podocytes and in glomeruli from diabetic mice. The podocyte specific Clock knockout mice at age 3 months and 8 months showed deficient autophagy, loss of podocytes and increased albuminuria. Chromatin immunoprecipitation (CHIP) sequence and PCR analysis indicated Clock binding to the promoter regions of Becn1 and Atg12. ChIP-qpcr analysis also confirmed the binding of Clock and autophagy gene promoter reduced when exposed to high glucose. Deletion Clock in podocyte could aggravate podocyte injury and proteinuria in diabetic mice. The autophagy in podocyte-clock-/- diabetic mice was lower than that of control diabetic mice.

Conclusion

Our findings demonstrate that clock-dependent regulating autophagy is essential for podocyte survival. The loss of circadian control autophagy plays an important role of podocyte injury and proteinuria.

Funding

  • Government Support – Non-U.S.