Compensatory hypertrophy of the kidney contributes to loss of klotho kidney through pakt signaling

Abstract Background and Aims Chronic kidney disease (CKD) represents a significant public health burden worldwide, mainly driven by the increase of the incidence of associated risk factors like diabetes. Decreased renal Klotho expression is an early feature of CKD, driving an increase on circulating FGF23 and phosphate. These alterations in mineral metabolism have a direct negative impact on the progression of renal dysfunction and can cause bone alterations, vascular calcification and heart failure. In parallel, during the early stages of CKD, kidneys activate molecular mechanisms of hypertrophy in an attempt to counteract the loss of renal function. The PI3K/Akt/mTOR pathway, activated by growing factors like insulin-like growing factor-1 (IGF-1) participates in compensatory renal growth. The aim of the present study is to investigate the possible role of PI3K/Akt activation on renal Klotho levels during renal compensatory hypertrophy. Method We generated a mice model of kidney compensatory hypertrophy (UNX mice) in which kidney klotho levels and circulating mineral metabolism parameters were analyzed. Furthermore, some of the mice were treated with inhibitors of the PI3K/Akt/mTOR pathway. In vitro, proximal tubular epithelial human cells (PTEC) were stimulated with IGF-1 in order to activate the PI3K/Akt pathway, and the effects on Klotho expression were determined. Results UNX mice present with an activation of the PI3K/Akt/mTOR pathway in kidney, which correlates with the loss on renal Klotho expression. Moreover, UNX mice showed an increase on both, plasma phosphate and FGF23, and a decrease in the fractional excretion of phosphate (% FEPi). Renal function, estimated by BUN plasma levels, was unaltered. Pharmacological inhibition of the pathway restored Klotho and decreased FGF23 levels, normalizing renal phosphate excretion and blood levels. In vitro, IGF-1 stimulated PI3K/Akt activation in PTEC and induced a decline on Klotho expression, which was restored with PI3K/AKT inhibitors. Conclusion The overactivation of PI3K/Akt/mTOR pathway in renal hypertrophy modulates Klotho expression and has direct effects on FGF23 and phosphate. Our findings constitute an important breakthrough in the research of new therapeutic targets in order to maintain renal Klotho levels, and it may be useful in the treatment of kidney disease patients.