Rapamycin downregulates α-klotho in the kidneys of female rats with normal and reduced renal function

Area of Science:

• Nephrology
• Endocrinology
• Aging Research

Background:

• Mammalian target of rapamycin (mTOR) and alpha-klotho (α-klotho) are implicated in kidney disease pathophysiology, mineral metabolism, and aging.
• The effect of mTOR inhibition on renal α-klotho expression remains largely unknown.

Purpose of the Study:

• To investigate the impact of mTOR inhibition by rapamycin on renal α-klotho expression in rats with varying renal function and dietary phosphorus intake.

Main Methods:

• Rats with normal and reduced renal function (Nx) were administered rapamycin (1.3 mg/kg/day) for 22 days.
• Experiments utilized diets with normal (0.6% P) and low (0.2% P) phosphorus content.
• Measurements included phosphaturia, FGF23 levels, and renal α-klotho expression (mRNA and protein) via RT-qPCR, Western Blot, and immunohistochemistry.

Main Results:

• Rapamycin induced phosphaturia in both control and Nx rats, irrespective of diet.
• A decrease in FGF23 was observed in control rats post-rapamycin treatment.
• Rapamycin significantly down-regulated renal α-klotho mRNA and protein levels in both control and Nx rats, particularly noticeable in rats fed a normal phosphorus diet.
• Renal α-klotho expression showed a significant inverse correlation with urinary phosphorus excretion (r = -0.525, p = 0.0002).

Conclusions:

• Rapamycin administration promotes phosphaturia and reduces renal α-klotho expression in rats with normal and compromised renal function.
• These effects are observable across different dietary phosphorus levels, highlighting a potential mechanism linking mTOR inhibition to altered mineral metabolism and kidney health.