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Abstract: SA-OR11

p53/MicroRNA-214/ULK1 Axis Impairs Renal Tubular Autophagy in Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Ma, Zhengwei, Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Augusta, Georgia, United States
  • Li, Lin, Department of Nephrology, Changzheng Hospital, Second Military Medical University, Shanghai, China
  • Livingston, Man J., Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Augusta, Georgia, United States
  • Mei, Changlin, Department of Nephrology, Changzheng Hospital, Second Military Medical University, Shanghai, China
  • Dong, Zheng, Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Augusta, Georgia, United States
Background

The pathogenesis of diabetic kidney disease (DKD) is unclear. Dysregulation of autophagy in DKD has been reported, but the underlying mechanism and its pathogenic role in DKD remain elusive.

Methods

Autophagy changes in DKD were investigated in high glucose treated renal tubular cells in vitro and in Akita mice and streptozotocin (STZ)-induced diabetic mice in vivo. Autophagy-related gene 7 (Atg7), microRNA-214 (miR-214), or p53 were ablated specifically from kidney proximal tubules to elucidate the pathogenic role and underlying mechanism of autophagy dysregulation in DKD. The expression of autophagy-related proteins, miR-214, and p53 were analyzed in human diabetic kidney tissues along with renal pathologies to determine their correlations.

Results

Autophagy was inhibited in DKD models and in human diabetic kidneys. Ablation of Atg7 from kidney proximal tubules led to autophagy deficiency and worsened renal hypertrophy, tubular damage, inflammation, fibrosis, and albuminuria in diabetic mice, indicating a protective role of autophagy in DKD. Autophagy impairment in DKD was associated with the downregulation of ULK1, a key serine/threonine protein kinase for the initiation of autophagy. ULK1 downregulation in DKD involved miR-214, which was induced in diabetic kidney cells and tissues to repress ULK1 expression. Ablation of miR-214 from kidney proximal tubules prevented ULK1 decrease and autophagy impairment in diabetic kidneys, resulting in less renal hypertrophy and albuminuria. Furthermore, blockade of p53 attenuated miR-214 induction in DKD, leading to higher levels of ULK1 and autophagy, accompanied by the amelioration of DKD. Compared to non-diabetic samples, renal biopsies from human diabetic patients showed the induction of p53 and miR-214, associated by the downregulation of ULK1 and autophagy. There was a significant positive correlation between p53/miR-214 and renal fibrosis, whereas a negative correlation between ULK1/LC3 and renal fibrosis in diabetic patients.

Conclusion

Autophagy dysfunction occurs in renal tubules in DKD, and contributes to renal hypertrophy and related pathologies. Mechanistically, p53 is activated in DKD to induce miR-214, which represses ULK1 resulting in autophagy dysfunction. The results identify the p53/miR-214/ULK1 axis of autophagy impairment for the development and progression of DKD.

Funding

  • Other NIH Support