Common Kidney-Protective Drugs Show Wildly Different Effects on Anti-Aging Protein Klotho

Klotho is a kidney-derived protein widely recognized for its anti-aging, anti-fibrotic, and anti-inflammatory properties. It acts as a co-receptor for FGF23 and helps regulate phosphate excretion and vitamin D metabolism. Declining Klotho levels are associated with aging, chronic kidney disease (CKD), and cardiovascular deterioration. Mineralocorticoid receptor (MR) antagonists—used to treat heart failure, CKD, and hypertension—share some overlapping benefits with Klotho, including anti-fibrotic and anti-inflammatory effects. This study asked whether these drugs might be working partly by modulating Klotho production.

Researchers at the University of Hohenheim exposed four renal cell lines—MDCK (canine), NRK-52E (rat), HK2 (human), and primary human RPTECs—to aldosterone and four MR antagonists: spironolactone, eplerenone, finerenone, and esaxerenone. Klotho mRNA was measured by qRT-PCR and protein levels confirmed by Western blotting. Cell lines were verified to express the mineralocorticoid and androgen receptors, though progesterone receptor expression was absent in MDCK cells.

Aldosterone had no significant effect on Klotho expression in any cell line, even when potentially confounding serum steroids were removed by using charcoal-stripped FBS. Eplerenone also produced no significant changes. Spironolactone, however, produced strikingly divergent results: it dose-dependently increased Klotho mRNA in MDCK and NRK-52E cells, but decreased both Klotho mRNA and protein in HK2 human kidney cells and primary RPTECs. Because spironolactone—unlike eplerenone—has significant affinity for the androgen receptor and progesterone receptor, the authors tested testosterone, progesterone, flutamide, and mifepristone to probe whether off-target receptor activity could explain the divergent effects. Results suggested androgen and progesterone receptor involvement may partly account for spironolactone's cell-specific actions. Finerenone, the novel non-steroidal MR antagonist with high receptor selectivity and a favorable clinical safety profile, dose-dependently reduced Klotho in MDCK and NRK-52E cells, and at low doses also in HK2 cells. Esaxerenone effects varied by cell line with less consistent patterns.

These findings carry important implications for clinical practice. Finerenone is now approved and increasingly prescribed for CKD and heart failure with preserved ejection fraction—conditions where Klotho is already significantly reduced. If finerenone suppresses Klotho in the kidney, some of its organ-protective benefits could be partially offset. Conversely, spironolactone's Klotho-upregulating effect in some cell types may contribute to its efficacy in non-human model systems, though its Klotho-reducing effect in human cell lines is a concern. The complete lack of effect by aldosterone and eplerenone on Klotho suggests these relationships are not simply mediated through classical MR genomic signaling.

Key limitations include the exclusive use of in vitro cell culture models, which may not replicate the complexity of the intact kidney or systemic hormonal environment. Species differences between cell lines complicate direct clinical translation. The partial text available does not detail esaxerenone or RPTEC data fully, and the mechanisms underlying cell-line-specific divergence remain incompletely elucidated. In vivo studies are needed to determine whether these Klotho-modulating effects are physiologically relevant.