TY - JOUR
T1 - P53/microRNA-214/ULK1 axis impairs renal tubular autophagy in diabetic kidney disease
AU - Ma, Zhengwei
AU - Li, Lin
AU - Livingston, Man J.
AU - Zhang, Dongshan
AU - Mi, Qingsheng
AU - Zhang, Ming
AU - Ding, Han Fei
AU - Huo, Yuqing
AU - Mei, Changlin
AU - Dong, Zheng
N1 - Funding Information:
We thank Eric Olson and Joseph Hill at The University of Texas Southwestern Medical Center (Dallas, Texas, USA) for providing miR-214-floxed mice and CAG-RFP-GFP-LC3-transgenic mice, respectively. We also thank Volker Haase at Vanderbilt University School of Medicine (Nashville, Tennessee, USA) for providing the PEPCK-Cre mouse line. This study was supported in part by grants from the US Department of Veterans Affairs (Merit Review Award I01 BX000319) and the NIH (DK058831 and DK087843). ZD is a recipient of a Senior Research Career Scientist award from the US Department of Veterans Affairs.
Funding Information:
We thank Eric Olson and Joseph Hill at The University of Texas Southwestern Medical Center (Dallas, Texas, USA) for providing miR-214–floxed mice and CAG-RFP-GFP-LC3–transgenic mice, respectively. We also thank Volker Haase at Vanderbilt University School of Medicine (Nashville, Tennessee, USA) for providing the PEPCK-Cre mouse line. This study was supported in part by grants from the US Department of Veterans Affairs (Merit Review Award I01 BX000319) and the NIH (DK058831 and DK087843). ZD is a recipient of a Senior Research Career Scientist award from the US Department of Veterans Affairs.
Publisher Copyright:
© 2020, American Society for Clinical Investigation.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - Dysregulation of autophagy in diabetic kidney disease (DKD) has been reported, but the underlying mechanism and its pathogenic role remain elusive. We show that autophagy was inhibited in DKD models and in human diabetic kidneys. Ablation of autophagy-related gene 7 (Atg7) from kidney proximal tubules led to autophagy deficiency and worse 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 unc-51-like autophagyactivating kinase 1 (ULK1), which was mediated by the upregulation of microRNA-214 (miR-214) in diabetic kidney cells and tissues. Ablation of miR-214 from kidney proximal tubules prevented a decrease in ULK1 expression 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 an amelioration of DKD. Compared with nondiabetic samples, renal biopsies from patients with diabetes showed induction of p53 and miR-214, associated with downregulation of ULK1 and autophagy. We found a positive correlation between p53/miR-214 and renal fibrosis, but a negative correlation between ULK1/LC3 and renal fibrosis in patients with diabetes. Together, these results identify the p53/ miR-214/ULK1 axis in autophagy impairment in diabetic kidneys, pinpointing possible therapeutic targets for DKD.
AB - Dysregulation of autophagy in diabetic kidney disease (DKD) has been reported, but the underlying mechanism and its pathogenic role remain elusive. We show that autophagy was inhibited in DKD models and in human diabetic kidneys. Ablation of autophagy-related gene 7 (Atg7) from kidney proximal tubules led to autophagy deficiency and worse 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 unc-51-like autophagyactivating kinase 1 (ULK1), which was mediated by the upregulation of microRNA-214 (miR-214) in diabetic kidney cells and tissues. Ablation of miR-214 from kidney proximal tubules prevented a decrease in ULK1 expression 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 an amelioration of DKD. Compared with nondiabetic samples, renal biopsies from patients with diabetes showed induction of p53 and miR-214, associated with downregulation of ULK1 and autophagy. We found a positive correlation between p53/miR-214 and renal fibrosis, but a negative correlation between ULK1/LC3 and renal fibrosis in patients with diabetes. Together, these results identify the p53/ miR-214/ULK1 axis in autophagy impairment in diabetic kidneys, pinpointing possible therapeutic targets for DKD.
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U2 - 10.1172/JCI135536
DO - 10.1172/JCI135536
M3 - Article
C2 - 32804155
AN - SCOPUS:85090250084
SN - 0021-9738
VL - 130
SP - 5011
EP - 5026
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 9
ER -
