Aged Adrenal Glands Promote Kidney Aging in a Murine Model of Heterochronic Adrenal Transplantation: Role of Age-Related Autonomous Aldosteronism

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Background: Inter-organ communication (IOC) involves the exchange of signals and substances between different organs, playing a vital role in maintaining overall health and homeostasis. Dysregulated IOC is linked to aging and contributes to age-related functional declines and pathological changes across various organs. The adrenal glands, by secreting crucial hormones such as cortisol, aldosterone, and adrenaline, play a key role in IOC and in regulating physiological homeostasis. However, how adrenal gland-mediated IOC regulates kidney aging remains unclear. Methods: Young mice (3 months old) received adrenal transplants from 15-mon-old aged mice or from isochronic controls, and were followed for 2 months. Urine, serum, and kidney specimens were collected and analyzed. Results: Young mice that received adrenal transplants from aged mice exhibited a mild increased albuminuria compared to those receiving isochronic adrenal transplants. Histological analysis revealed that the transplantation of aged adrenals resulted in slight glomerular enlargement, modest expansion of glomerular mesangium, and a tendency toward increased accumulation of extracellular matrix in the glomeruli and renal tubulointerstitium. This was associated with early signs of kidney aging and renal cell senescence, as indicated by increased senescence-associated β-galactosidase activity, enhanced expression of senescence mediators such as p16INK4A and p21, and a trend toward reduced expression of synaptopodin in glomeruli and diminished klotho expression in renal tubules. Mechanistically, the aged adrenal glands displayed disrupted linear continuous expression of aldosterone synthase (CYP11B2) but exhibited clusters of CYP11B2-expressing cells in the zona glomerulosa, suggesting the formation of aldosterone-producing cell clusters. Consistent with this, the serum aldosterone-to-renin ratio was elevated in both aged mice and young mice receiving aged adrenal transplants, indicating age-related autonomous aldosteronism. Conclusion: Aged adrenal glands, containing aldosterone-producing cell clusters, may promote kidney aging through autonomous, renin-independent aldosterone production. Funding: NIDDK Support

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