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Κυριακή 18 Ιουλίου 2021

Death-associated protein kinase 1 correlates with podocyte apoptosis and renal damage and can be mediated by miR-361

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Histol Histopathol. 2021 Jul 16:18358. doi: 10.14670/HH-18-358. Online ahead of print.

ABSTRACT

BACKGROUND: Herein, we aimed to determine whether DAPK1 and its post-transcriptional regulator miR-361 were implicated in high glucose (HG)-induced podocyte injury and renal damage in db/db mice.

MATERIALS AND METHODS: Podocytes were incubated with normal glucose (NG; 5 mM) or HG (30 mM). Podocyte apoptosis was evaluated using TUNEL staining. Lentiviral-delivered specific short hairpin RNA (shRNA) was designed to silence DAPK1 expression in podocytes. miR-361 agomir was administrated by tail intravenous injection in db/db diabetic mice to investigate the renoprotection of miR-361 in vivo.

RESULTS: Exposure of podocytes to HG led to a significant increase in DAPK1 mRNA and protein levels and a decrease in miR-361 expression levels. Knockdown of DAPK1 attenuated HG-triggered growth inhibition, apoptosis, DNA damage and cell membran e damage in podocytes. Mechanically, DAPK1 was a direct target of miR-361. Transfection with miR-361 mimics into podocytes resulted in a significant decrease in the DAPK1 protein expression level. In addition, HG-induced the up-regulation of the DAPK1 protein expression level in podocytes was restrained by miR-361 mimics transfection. Intriguingly, overexpression of DAPK1 in HG-stimulated podocytes muted miR-361-mediated cytoprotection, including anti-apoptosis, resistance to DNA and membrane damage. In vivo, overexpression of miR-361 protected against hyperglycemia-induced podocyte loss, tubular atrophy and interstitial fibrosis in the kidney of db/db mice. Moreover, overexpression of miR-361 inhibited the protein expression of DAPK1 in the kidney of db/db mice.

CONCLUSION: Our research presented a novel mechanism of HG-induced podocyte damage or renal lesion, supporting the miR-361/DAPK1 signaling pathway that could be used as a potential therapeutic target for the treatment of DN.

PMID:34269397 | DOI:10.14670/HH-18-358

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