Spironolactone ameliorates PIT1-dependent vascular osteoinduction in klotho-hypomorphic mice

Voelkl, Jakob; Alesutan, Ioana; Leibrock, Christina; Quintanilla-Martı́nez, Leticia; Kühn, Volker; Feger, Martina; Mia, Sobuj; Ahmed, Mohamed S.; Rosenblatt, Kevin P.; Kuro‐o, Makoto; Läng, Florian

doi:10.1172/jci64093

Cited by 109 publications

(160 citation statements)

References 75 publications

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“…4 The decrease of plasma aldosterone concentration after NH 4 Cl treatment could have contributed to the decrease of vascular calcification, because aldosterone stimulates vascular osteoinduction, an effect at least in part due to upregulation of Pit1 expression. 16 However, the survival benefit of aldosterone receptor blockade by spironolactone is only modest in kl/kl mice. 16 Thus, reversal of hyperaldosteronism presumably contributes to, but does not fully account for, the spectacular survival benefit and phenotypic recovery of kl/kl mice by NH 4 Cl treatment.…”

Section: Discussionmentioning

confidence: 99%

“…16 However, the survival benefit of aldosterone receptor blockade by spironolactone is only modest in kl/kl mice. 16 Thus, reversal of hyperaldosteronism presumably contributes to, but does not fully account for, the spectacular survival benefit and phenotypic recovery of kl/kl mice by NH 4 Cl treatment. In wild-type mice, the plasma aldosterone and ADH concentrations were low and not significantly modified by NH 4 Cl treatment.…”

Section: Discussionmentioning

confidence: 99%

“…14 The excessive tissue calcification of kl/kl mice and patients with CKD is associated with osteogenic differentiation of vascular smooth muscle cells as well as increased expression of the osteogenic transcription factor Core binding factor a-1 (Cbfa1), which triggers transformation of mesenchymal cells into osteoblast-and chondroblast-like cells. 1,15 Cbfa1 stimulates the expression of alkaline phosphatase, 1,16,17 which fosters calcification by degradation of the inhibitor pyrophosphate. 18,19 Osteoinductive reprogramming of vascular smooth muscle cells is stimulated by aldosterone and fostered by hyperaldosteronism of kl/kl mice.…”

mentioning

confidence: 99%

“…18,19 Osteoinductive reprogramming of vascular smooth muscle cells is stimulated by aldosterone and fostered by hyperaldosteronism of kl/kl mice. 16 Phosphate-induced osteoinductive reprogramming is closely intertwined with cellular senescence. 20,21 Along those lines, klotho deficiency fosters cellular senescence and Tnfainduced senescence can be countered by klotho supplementation.…”

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confidence: 99%

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NH4Cl Treatment Prevents Tissue Calcification in Klotho Deficiency

Leibrock¹,

Alesutan²,

Voelkl³

et al. 2015

Journal of the American Society of Nephrology

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Klotho, a cofactor in suppressing 1,25(OH) 2 D 3 formation, is a powerful regulator of mineral metabolism. Klotho-hypomorphic mice (kl/kl) exhibit excessive plasma 1,25(OH) 2 D 3 , Ca 2+ , and phosphate concentrations, severe tissue calcification, volume depletion with hyperaldosteronism, and early death. Calcification is paralleled by overexpression of osteoinductive transcription factor Runx2/Cbfa1, Alpl, and senescenceassociated molecules Tgfb1, Pai-1, p21, and Glb1. Here, we show that NH 4 Cl treatment in drinking water (0.28 M) prevented soft tissue and vascular calcification and increased the life span of kl/kl mice .12-fold in males and .4-fold in females without significantly affecting extracellular pH or plasma concentrations of 1,25(OH) 2 D 3 , Ca 2+ , and phosphate. NH 4 Cl treatment significantly decreased plasma aldosterone and antidiuretic hormone concentrations and reversed the increase of Runx2/Cbfa1, Alpl, Tgfb1, Pai-1, p21, and Glb1 expression in aorta of kl/kl mice. Similarly, in primary human aortic smooth muscle cells (HAoSMCs), NH 4 Cl treatment reduced phosphate-induced mRNA expression of RUNX2/CBFA1, ALPL, and senescence-associated molecules. In both kl/kl mice and phosphate-treated HAoSMCs, levels of osmosensitive transcription factor NFAT5 and NFAT5-downstream mediator SOX9 were higher than in controls and decreased after NH 4 Cl treatment. Overexpression of NFAT5 in HAoSMCs mimicked the effect of phosphate and abrogated the effect of NH 4 Cl on SOX9, RUNX2/CBFA1, and ALPL mRNA expression. TGFB1 treatment of HAoSMCs upregulated NFAT5 expression and prevented the decrease of phosphate-induced NFAT5 expression after NH 4 Cl treatment. In conclusion, NH 4 Cl treatment prevents tissue calcification, reduces vascular senescence, and extends survival of klotho-hypomorphic mice. The effects of NH 4 Cl on vascular osteoinduction involve decrease of TGFB1 and inhibition of NFAT5-dependent osteochondrogenic signaling.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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NH4Cl Treatment Prevents Tissue Calcification in Klotho Deficiency

Leibrock¹,

Alesutan²,

Voelkl³

et al. 2015

Journal of the American Society of Nephrology

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“…As has been shown in Klotho-deficient mice, insufficient renal expression of aKlotho is associated with a high serum concentration of FGF23 (51). We therefore analyzed renal aKlotho expression by Western blot analysis.…”

Section: Resultsmentioning

confidence: 89%

Enhanced FGF23 production in mice expressing PI3K‐insensitive GSK3 is normalized by β‐blocker treatment

Fajol¹,

Chen²,

Umbach³

et al. 2015

FASEB j.

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Glycogen synthase kinase (GSK)-3 is a ubiquitously expressed kinase inhibited by insulindependent Akt/PKB/SGK. Mice expressing Akt/PKB/ SGK-resistant GSK3a/GSK3b (gsk3 KI ) exhibit enhanced sympathetic nervous activity and phosphaturia with decreased bone density. Hormones participating in phosphate homeostasis include fibroblast growth factor (FGF)-23, a bone-derived hormone that inhibits 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ; calcitriol) formation and phosphate reabsorption in the kidney and counteracts vascular calcification and aging. FGF23 secretion is stimulated by the sympathetic nervous system. We studied the role of GSK3-controlled sympathetic activity in FGF23 production and phosphate metabolism. Serum FGF23, 1,25(OH) 2 D 3 , and urinary vanillylmandelic acid (VMA) were measured by ELISA, and serum and urinary phosphate and calcium were measured by photometry in gsk3 KI and gsk3 WT mice, before and after 1 wk of oral treatment with the b-blocker propranolol. Urinary VMA excretion, serum FGF23, and renal phosphate and calcium excretion were significantly higher, and serum 1,25(OH) 2 D 3 and phosphate concentrations were lower in gsk3 KI mice than in gsk3 WT mice. Propranolol treatment decreased serum FGF23 and loss of renal calcium and phosphate and increased serum phosphate concentration in gsk3 KI mice. We conclude that Akt/ PKB/SGK-sensitive GSK3 inhibition participates in the regulation of FGF23 release, 1,25(OH) 2 D 3 formation, and thus mineral metabolism, by controlling the activity of the sympathetic nervous system.-Fajol, A., Chen, H., Umbach, A. T., Quarles, L. D., Lang, F., Föller, M. Enhanced FGF23 production in mice expressing PI3K-insensitive GSK3 is normalized by b-blocker treatment. Insulin mainly regulates glucose homeostasis, but also affects renal phosphate handling (1, 2). Cellular insulin's effects are in large part mediated by activation of PI3K resulting in the stimulation of Akt/PKB and serum-and glucocorticoid-inducible kinase (SGK) isoforms (3, 4). Upon activation, Akt/PKB (5) and SGK (6, 7) isoforms can phosphorylate numerous cellular targets, including glycogen synthase kinase (GSK)-3, thereby rendering this kinase inactive. Loss of Akt2 or of SGK3 activity in mouse models results in decreased renal phosphate reabsorption and, hence, phosphate loss (8, 9). Moreover, transgenic mice expressing Akt/PKB/SGK-resistant GSK3a/b [gsk-3 knockin (gsk-3 KI )] have hypophosphatemia, phosphaturia, and decreased bone density, illustrating the significance of PI3K signaling for renal phosphate handling (10). A direct inhibitory effect of GSK3 on renal sodium-dependent phosphate transporter IIa (NaPiIIa) (10) is likely to contribute to the phosphaturia of gsk-3 KI mice, but may not fully explain it. Gsk-3 KI mice also have hypertension and a faster heart rate caused by enhanced sympathetic activity (11).Fibroblast growth factor (FGF)-23 is a bone-derived hormone that controls phosphate and calcium metabolism (12-14). Its main target is the kidney, where FGF23 inhibits tubular p...

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Targeting efficacy of spironolactone in patients with heart failure with preserved ejection fraction: the TOPCAT study

et al. 2022

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Aims We aimed to explore the heterogeneous treatment effects (HTEs) for spironolactone treatment in patients with Heart failure with preserved ejection fraction (HFpEF) and examine the efficacy and safety of spironolactone medication, ensuring a better individualized therapy. Methods and results We used the causal forest algorithm to discover the heterogeneous treatment effects (HTEs) from patients in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. Cox regressions were performed to assess the hazard ratios (HRs) of spironolactone medication for cardiovascular death and drug discontinuation in each group. The causal forest model revealed three representative covariates and participants were partitioned into four subgroups which were Group 1 (baseline BMI ≤ 31.71 kg/m 2 and baseline ALP ≤ 80 U/L, n = 759); Group 2 (BMI ≤ 31.71 kg/m 2 and ALP > 80 U/L, n = 1088); Group 3 (BMI > 31.71 kg/m 2 , and WBC ≤ 6.6 cells/μL, n = 633); Group 4 (BMI > 31.71 kg/m 2 and WBC > 6.6 cells/μL, n = 832), respectively. In the four subgroups, spironolactone therapy reduced the risk of cardiovascular death in high‐risk group (Group 4) with both high BMI and WBC count (HR: 0.76; 95% CI 0.58 to 0.99; P = 0.045) but increased the risk in low‐risk group (Group 1) with both low BMI and ALP (HR: 1.45; 95% CI 1.02 to 2.07; P = 0.041; P for interaction = 0.020) but showed similar risk of drug discontinuation ( P for interaction = 0.498). Conclusion Our study manifested the HTEs of spironolactone in patients with HFpEF. Spironolactone treatment in HFpEF patients is feasible and effective in patients with high BMI and WBC while harmful in patients with low BMI and ALP. Machine learning model could be meaningful for improved categorization of patients with HFpEF, ensuring a better individualized therapy in the clinical setting.

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Spironolactone ameliorates PIT1-dependent vascular osteoinduction in klotho-hypomorphic mice

Cited by 109 publications

References 75 publications

NH4Cl Treatment Prevents Tissue Calcification in Klotho Deficiency

NH4Cl Treatment Prevents Tissue Calcification in Klotho Deficiency

Enhanced FGF23 production in mice expressing PI3K‐insensitive GSK3 is normalized by β‐blocker treatment

Targeting efficacy of spironolactone in patients with heart failure with preserved ejection fraction: the TOPCAT study

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