AKT2 is essential to maintain podocyte viability and function during chronic kidney disease

Abstract

In chronic kidney disease (CKD), loss of functional nephrons results in metabolic and mechanical stress in the remaining ones, resulting in further nephron loss. Here we show that Akt2 activation has an essential role in podocyte protection after nephron reduction. Glomerulosclerosis and albuminuria were substantially worsened in Akt2(-/-) but not in Akt1(-/-) mice as compared to wild-type mice. Specific deletion of Akt2 or its regulator Rictor in podocytes revealed that Akt2 has an intrinsic function in podocytes. Mechanistically, Akt2 triggers a compensatory program that involves mouse double minute 2 homolog (Mdm2), glycogen synthase kinase 3 (Gsk3) and Rac1. The defective activation of this pathway after nephron reduction leads to apoptosis and foot process effacement of the podocytes. We further show that AKT2 activation by mammalian target of rapamycin complex 2 (mTORC2) is also required for podocyte survival in human CKD. More notably, we elucidate the events underlying the adverse renal effect of sirolimus and provide a criterion for the rational use of this drug. Thus, our results disclose a new function of Akt2 and identify a potential therapeutic target for preserving glomerular function in CKD.

mTOR Regulates Endocytosis and Nutrient Transport in Proximal Tubular Cells

“…24 However, it has been recognized that long-term administration of rapamycin in high doses additionally inhibits mTORC2 and exerts cytotoxic effects. 25 In agreement, long-term follow-up studies (3 months) in our double-knockout RapRic DTubule mice showed a reduced MEGALIN expression, whereas Rap DTubule mice maintained a stable MEGALIN expression. Additionally, we detected a strong reduction in the overall renal cortex volume because of shortening of the S1/2 segment in Rap DTubule mice, and it was more pronounced in RapRic DTubule mice, confirming the importance of mTOR signaling for general cellular programs, such as cell growth, proliferation, and metabolism.…”

The Kidney as a Reservoir for HIV-1 after Renal Transplantation

“…Interestingly, this sequence of events is observed in different models of podocyte injury leading to the development of FSGS. 12,24,25 The exact mechanism is unknown, but certainly the genetic background of the donor and others parameters may affect the course of glomerular lesions. Indeed, on native kidneys, HIVAN has been linked to G1 and/or G2 APOL1 variants present in the AfricanAmerican population, 13 whereas Caucasians, who do not express these variants, display other various forms of glomerular lesions but usually have no features of HIVAN.…”

Molecular mechanisms of diabetic kidney disease

“…Genetic deletion of S6K1 prevented renal hypertrophy in diabetic mice (79). Furthermore, PTEN and Akt2 are likely to be upstream of mTOR and may also prove to be potential drug targets (80). mTOR signaling also regulates autophagy; mTOR inhibition stimulates the initial engulfment of intracellular organelles and formation of the autophagosome (81).…”