Beclin 1/Bcl-2 complex-dependent autophagy activity modulates renal susceptibility to ischemia-reperfusion injury and mediates renoprotection by Klotho.

Abstract

Klotho- and beclin 1-driven autophagy extends life. We examined the role of beclin 1 in modifying acute kidney injury (AKI) and whether beclin 1 mediates Klotho's known renoprotective action in AKI. AKI was induced by ischemia-reperfusion injury in mice with different levels of autophagy activity by genetic manipulation: wild-type (WT) mice with normal beclin 1 expression and function, mice with normal beclin 1 levels but high activity through knockin of gain-of-function mutant beclin 1 (Becn1F121A), mice with low beclin 1 levels and activity caused by heterozygous global deletion of beclin 1 (Becn1+/-), or mice with extremely low beclin 1 activity from knockin of the mutant constitutively active beclin 1 inhibitor Bcl-2 (Bcl2AAA). Klotho was increased by transgenic overexpression (Tg-Kl) or recombinant Klotho protein administration. After ischemia-reperfusion injury, Becn1F121A mice (high autophagy) had milder AKI and Becn1+/- and Bcl2AAA mice (low autophagy) had more severe AKI than WT mice. Tg-Kl mice had milder AKI, but its renoprotection was partially attenuated in Becn1+/-;Tg-Kl mice and was significantly reduced, although not completely abolished, in Bcl2AAA;Tg-Kl mice. Recombinant Klotho protein conferred more renoprotection from AKI in WT mice than in Becn1+/- or Bcl2AAA mice. Klotho reduced beclin 1/Bcl-2 protein complexes and increased autophagy activity, but this effect was less prominent in mice or cells with Bcl2AAA. Transfected Bcl2AAA or Becn1F123A decreased or increased autophagy activity and rendered cells more susceptible or more resistant to oxidative cytotoxicity, respectively. In conclusion, beclin 1 confers renoprotection by activating autophagy. Klotho protects the kidney partially via disruption of beclin 1/Bcl-2 interactions and enhancement of autophagy activity.

• Authors: Peng Li, Mingjun Shi, Jenny Maique, Joy Shaffer, Shirley Yan, Orson W Moe, Ming Chang Hu
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 318 Issue 3 Pg. F772-F792 (03 01 2020) ISSN: 1522-1466 [Electronic] United States
• PMID: 31984794 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Beclin-1
• Proto-Oncogene Proteins c-bcl-2
• Bcl2 protein, mouse
• Hydrogen Peroxide
• Glucuronidase
• Klotho Proteins

Topics

• Animals
• Autophagy (physiology)
• Beclin-1 (genetics, metabolism)
• Cell Line
• Gene Expression Regulation
• Genotype
• Glucuronidase (genetics, metabolism)
• Hydrogen Peroxide
• Kidney Diseases (etiology, metabolism)
• Klotho Proteins
• Mice
• Opossums
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Reperfusion Injury