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Abstract: TH-OR31

PI3K/AKT/mTOR Pathway Regulates Renal Expression of Klotho

Session Information

Category: Bone and Mineral Metabolism

  • 501 Bone and Mineral Metabolism: Basic

Authors

  • Perez-Gomez, Aurora, Institut de Recerca Biomedica de Lleida Fundacio Dr Pifarre, Lleida, Catalunya, Spain
  • Diaz Tocados, Juan M., Institut de Recerca Biomedica de Lleida Fundacio Dr Pifarre, Lleida, Catalunya, Spain
  • Domínguez Coral, Juan Diego, Institut de Recerca Biomedica de Lleida Fundacio Dr Pifarre, Lleida, Catalunya, Spain
  • Carrasco, Alicia Garcia, Institut de Recerca Biomedica de Lleida Fundacio Dr Pifarre, Lleida, Catalunya, Spain
  • Valdivielso, Jose M., Institut de Recerca Biomedica de Lleida Fundacio Dr Pifarre, Lleida, Catalunya, Spain
Background

Renal Klotho expression decreases early in chronic kidney disease (CKD), increasing circulating FGF23 and phosphate levels. This negatively affects renal disease progression and cardiovascular complications. Preserving renal Klotho expression is of interest, but the underlying mechanisms are unclear.During early stages of CKD, kidneys activate mechanisms of hypertrophy, in which the PI3K/Akt/mTOR pathway plays a role. This pathway is activated by growth factors such as insulin-like growth factor-1 (IGF-1). The main negative regulator of this pathway is PTEN, which reduces the activation of canonical insulin signaling. We aimed to investigate the role of PTEN and the PI3K/AKT/mTOR pathway in kidney Klotho levels and their possible implication in CKD.

Methods

We measured renal Klotho levels, circulating FGF23, and phosphate in mice lacking PTEN in renal proximal tubular cells (PTEC) and in HK2 cells in vitro. We also examined normal mice with models of decreased renal mass caused by uninephrectomy (UNX) and 5/6 nephrectomy (SNX). Additionally, we tested the effect of mTOR inhibition. Furthermore, we analyzed PTEN and Klotho expression in kidney samples from CKD patients.

Results

We found that PTEC with downregulated PTEN exhibited decreased Klotho expression both in vitro and in vivo, accompanied by increased mTOR activity. Animals with PTEN elimination in PTEC also showed increased circulating phosphate and FGF23 levels, as well as a decrease in the fractional excretion of phosphate. These alterations were normalized by treatment with rapamycin. Normal mice with UNX or SNX exhibited increased renal IGF-1 expression and activation of the PI3K/AKT/mTOR pathway. Furthermore, these mice showed a reduction in renal Klotho expression and an increase in circulating FGF23 and phosphate. Both of these alterations were restored with rapamycin administration.
In renal samples from CKD patients, we observed a positive correlation between the expression of PTEN, KLOTHO, and glomerular filtration rate (GFR).

Conclusion

The overactivation of the PI3K/AKT/mTOR pathway in PTEC modulates Klotho levels in the kidney. Our findings represent a significant advancement in the search for new therapeutic targets to maintain and prevent reductions in renal Klotho levels, potentially benefiting kidney disease patients.

Funding

  • Government Support – Non-U.S.