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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 ( Becn1 F121A ), 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 ( Bcl2 AAA ). Klotho was increased by transgenic overexpression ( Tg-Kl) or recombinant Klotho protein administration. After ischemia-reperfusion injury, Becn1 F121A  mice (high autophagy) had milder AKI and Becn1 +/−  and Bcl2 AAA  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 Bcl2 AAA ;Tg-Kl mice. Recombinant Klotho protein conferred more renoprotection from AKI in WT mice than in Becn1 +/−  or Bcl2 AAA  mice. Klotho reduced beclin 1/Bcl-2 protein complexes and increased autophagy activity, but this effect was less prominent in mice or cells with Bcl2 AAA . Transfected Bcl2 AAA  or Becn1 F123A  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.

american journal of physiology. renal physiology./american journal of physiology. renal physiology

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