p53/microRNA-214/ULK1 axis impairs renal tubular autophagy in diabetic kidney disease

Abstract

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.

Identifying cell-enriched miRNAs in kidney injury and repair

“…For example, within the individual cell populations we found that in the PDGFR-β + cells during late injury, there was substantial loss of enriched miR-143 and -145 and a significant increase in miR-199 and -214 ( Supplemental Figure 8 ). We and others have previously shown that miR-214 is involved in renal injury and fibrosis ( 1 , 26 – 28 ).…”

Epigenetics and Inflammation in Diabetic Nephropathy

“…M2 macrophages ameliorate podocyte injury is related to miR-25-3p ( Huang et al, 2020 ). It is found that autophagy deficiency in diabetic mice increases macrophage infiltration in proximal tubules ( Ma et al, 2020 ), and the induction of miR-214 enhances the autophagy impairment, thus aggravating renal inflammation ( Li et al, 2011 ). MiR-214 in monocytes is upregulated by AGEs, which in turn impairs the expression of the phosphatase and tensin homolog (PTEN) and delays spontaneous apoptosis of monocytes ( Li et al, 2011 ).…”

Classical molecule in diabetic kidney hypertrophy is linked to defects in self‐eating through fine‐tuning

“…Focusing on this topic, in a recent publication in Journal of Clinical Investigation, Ma et al 3 reported that p53 accumulation in the proximal tubule of diabetic kidneys is linked to kidney hypertrophy and damage through microribonucleic acid (miR)-mediated autophagy defects. The authors confirmed that autophagosome formation was impaired in the proximal tubules of Akita mice, a type 1 diabetic model due to insulin gene mutation, and a streptozotocin-induced type 1 diabetic mouse model.…”

“…p53 has been known to regulate autophagy in a two ways: (i) turning autophagy on; and (ii) turning autophagy off. As described, Ma et al 3 provided a novel pathomechanism in DKD through fusion of classical knowledge with novel molecular biology techniques, showing that p53 turns kidney tubular autophagy off and contributes to kidney damage in diabetes. However, at the same time, there are several limitations/questions in their findings.…”

“…In summary, the authors found that increased p53 in the tubular epithelium in diabetes causes renal hypertrophy by suppressing ULK1 and autophagy through miR-214 (Figure 1). Although some points require further investigation, the report by Ma et al 3 indicates that the p53/miR-214/ULK1 axis in the tubular epithelium sheds new light on the molecular mechanisms of DKD and provides a therapeutic target for diabetic nephropathy.…”