Inorganic Phosphate Activates the AKT/mTORC1 Pathway and Shortens the Life Span of an α‑Klotho–Deficient Model

Abstract

Inorganic phosphate (Pi) has been implicated in the pathogenesis of accelerated aging; however, the underlying mechanisms remain elusive. Herein, we demonstrated in cultured cells and in vivo that increased levels of extracellular Pi activated the AKT/mammalian target of rapamycin complex 1 (mTORC1) pathway by suppressing membrane-bound phosphatase and tensin homolog (PTEN) levels in a manner requiring the sodium-dependent Pi transporter PiT-1. High levels of extracellular Pi also led to phosphorylation of Ser/Thr clusters in the C-terminal tail of PTEN, which has been shown to dissociate PTEN from the membrane. Notably, blockade of mTORC1 activity by rapamycin treatment prolonged the life span of hyperphosphatemic a-Klotho-deficient (Kl 2/2 ) mice. Dietary correction of hyperphosphatemia or treatment with rapamycin also rescued the brown adipose tissue dysfunction and oxidative damage observed in Kl 2/2 mice. Furthermore, rapamycin treatment partially rescued these effects and extended the life span when Kl 2/2 mice were maintained on a high-phosphate diet. Finally, rapamycin reduced circulating Pi levels in Kl 2/2 mice, apparently by decreasing the localization of sodium-dependent Pi transport protein 2a at the renal brush border membrane. Therefore, the activation of mTORC1 may create a vicious loop that exacerbates the retention of Pi, which in turn may enhance oxidative damage and ultimately shorten the life span of Kl 2/2 mice. These results demonstrate that Pi has important roles in the aging process, and the blockade of mTORC1 may have therapeutic potential for premature aging-like symptoms associated with hyperphosphatemia.

Novel treatment strategies for chronic kidney disease: insights from the animal kingdom

“…Alternative treatment strategies to prevent vascular calcification could potentially be derived from comparative physiology studies. For example, agents that stimulate NRF2 (Box 1), block mTORC1 signalling (143) or reduce phosphate absorption, such as by inducing calcium phosphate precipitation in the gut with magnesium (144), should be tested for their ability to decrease extracellular phosphate levels.…”

Downregulation of kidney protective factors by inflammation: role of transcription factors and epigenetic mechanisms

“…Understanding the molecular mechanisms of Klotho anti-aging effects may provide clues into aging. Phosphate overload appears to play a key role (50,69). Acquired Klotho deficiency has been described at the earliest stage of CKD, category G1 CKD, in which GFR is normal, but there is other evidence of kidney injury such as albuminuria (Ͼ30 mg/g creatinine) (39).…”

Phosphate-dependent FGF23 secretion is modulated by PiT2/Slc20a2

“…Fibroblast growth factor 23 (Fgf23) is a bone-derived hormone, which acts in concert with its co-receptor αKlotho to regulate the serum inorganic phosphate (Pi) concentration and vitamin D metabolism [1] , [2] . Mutations in humans and mice preventing normal FGF23 bioactivity result in elevated serum Pi concentrations due to impaired urinary Pi excretion.…”

“…Interestingly, the presence of regulatory feedback loops operating between FGF23 and Pi/vitamin D has been suggested [1] , [12] . In humans, serum FGF23 levels have been associated with the amount of dietary Pi [13] , [14] , while intravenous infusion or acute duodenal Pi load were found to increase FGF23 levels in healthy humans [15] .…”