Antiaging Gene Klotho Regulates Adrenal CYP11B2 Expression and Aldosterone Synthesis

Area of Science:

• Endocrinology
• Nephrology
• Genetics

Background:

• Klotho (KL) deficiency is linked to renal damage and hypertension via unknown mechanisms.
• Aldosterone synthesis, regulated by CYP11B2, plays a critical role in blood pressure.
• The relationship between Klotho and aldosterone production is not well understood.

Purpose of the Study:

• To investigate whether Klotho regulates the expression of CYP11B2, a key enzyme in aldosterone synthesis.
• To elucidate the role of Klotho in the development of hypertension and renal damage associated with CYP11B2 upregulation.

Main Methods:

• Assessed plasma aldosterone levels and blood pressure in Klotho haplodeficient (KL(+/-)) mice.
• Utilized eplerenone to block aldosterone actions and evaluate its effect on hypertension and kidney damage.
• Examined CYP11B2 protein expression in adrenal glands and human adrenocortical cells.
• Investigated the impact of KL manipulation on transcription factors SF-1 and ATF2.

Main Results:

• KL(+/-) mice exhibited elevated plasma aldosterone and persistent hypertension by 16 weeks of age.
• Aldosterone blockade reversed hypertension and attenuated kidney damage in KL-deficient mice.
• CYP11B2 expression was upregulated in the adrenal cortex of KL(+/-) mice, with KL and CYP11B2 colocalizing in zona glomerulosa cells.
• KL silencing upregulated CYP11B2 in human cells, while KL overexpression downregulated it, involving SF-1 and ATF2 pathways.

Conclusions:

• Klotho regulates CYP11B2 expression in adrenal glands.
• KL deficiency-induced hypertension and renal damage are partly mediated by increased CYP11B2 expression and subsequent aldosterone synthesis.
• This study identifies a novel mechanism linking Klotho, aldosterone, and cardiovascular/renal health.