In vivo evidence for therapeutic applications of beclin 1 to promote recovery and inhibit fibrosis after acute kidney injury.

Mingjun Shi, Jenny Maique, Sierra Shepard, Peng Li, Olivia Seli, Orson W Moe, Ming Chang Hu

Kidney international 2022 Jan

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Autophagy regulator beclin 1 activity determines the severity of kidney damage induced by ischemia reperfusion injury, but its role in kidney recovery and fibrosis are unknown and its therapeutic potentials have not been tested. Here, we explored beclin 1 effects on kidney fibrosis in three models of acute kidney injury (AKI)-ischemia reperfusion injury, cisplatin kidney toxicity, and unilateral ureteric obstruction in mouse strains with three levels of beclin 1 function: normal (wild type), low (heterozygous global deletion of beclin 1, Becn1+/-), and high beclin 1 activity (knockin gain-of-function mutant Becn1, Becn1FA). Fourteen days after AKI induction, heterozygous mice had more, but knockin mice had less kidney fibrosis than wild-type mice did. One day after ischemia reperfusion injury, heterozygous pan-kidney tubular Becn1 null mice had more severe kidney damage than homozygous distal tubular Becn1 null mice did, which was similar to the wild-type mice, implying that proximal tubular beclin 1 protects the kidney against ischemia reperfusion injury. By 14 days, both pan-kidney heterozygous Becn1 null and distal tubular homozygous Becn1 null mice had poorer kidney recovery than wild-type mice did. Injection of beclin 1 peptides increased cell proliferation in kidney tubules in normal mice. Beclin 1 peptides injection either before or after (2-5 days) ischemia reperfusion injury protected the kidney from injury and suppressed kidney fibrosis. Thus, both endogenous beclin 1 protein expression in kidney tubules and exogenous beclin 1 peptides are kidney protective via attenuation of acute kidney damage, promotion of cell proliferation, and inhibition of kidney fibrosis, consequently improving kidney recovery post-AKI. Hence, exogenous beclin 1 peptide may be a potential new therapy for AKI. Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Citation

Mingjun Shi, Jenny Maique, Sierra Shepard, Peng Li, Olivia Seli, Orson W Moe, Ming Chang Hu. In vivo evidence for therapeutic applications of beclin 1 to promote recovery and inhibit fibrosis after acute kidney injury. Kidney international. 2022 Jan;101(1):63-78