Angiotensin II blockade upregulates the expression of Klotho, the anti-ageing gene, in an experimental model of chronic cyclosporine nephropathy

Yoon, Hye Eun; Ghee, Jung Yeon; Piao, Shang Guo; Song, Jin Kyung; Han, Dong He; Kim, Sol; Ohashi, Naro; Kobori, Hiroyuki; Kuro‐o, Makoto; Yang, Chul Woo

doi:10.1093/ndt/gfq537

Cited by 158 publications

(132 citation statements)

References 58 publications

(65 reference statements)

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“…Along this line, it is worth mentioning that, in patients with CKD, plasma FGF23 levels are inversely related with NO-dependent vasodilation 16 and predict progression to ESRD. 17 On the other hand, the coreceptor of FGF23, Klotho-a well recognized renoprotective factor 18 -19 that attenuates angiotensin-II-induced renal damage 20 -is downregulated at an early stage in CKD patients. Klotho Ϫ/Ϫ mice suffer premature aging, and this phenotype may be corrected with a low phosphate diet.…”

Section: Discussionmentioning

confidence: 99%

Phosphate May Promote CKD Progression and Attenuate Renoprotective Effect of ACE Inhibition

Zoccali

Ruggenenti

Perna

et al. 2011

Journal of the American Society of Nephrology

195

131

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Phosphate may promote the onset and progression of chronic nephropathies. Here we evaluated the relationships between baseline serum phosphate levels, disease progression, and response to ACE inhibition in 331 patients with proteinuric nephropathies in the prospective Ramipril Efficacy In Nephropathy (REIN) trial. Independent of treatment, patients with phosphate levels in the highest two quartiles progressed significantly faster either to ESRD or to a composite endpoint of doubling of serum creatinine or ESRD compared with patients with phosphate levels below the median (P Ͻ 0.001). Results were similar when we analyzed phosphate as a continuous variable (P Յ 0.004). The renoprotective effect of ramipril decreased as serum phosphate increased (P Յ 0.008 for interaction); this modification of the treatment effect by phosphate persisted despite adjusting for potential confounders such as GFR and urinary protein. In summary, these data suggest that phosphate is an independent risk factor for progression of renal disease among patients with proteinuric CKD, and high levels of phosphate may even attenuate the renoprotective effect of ACE inhibitors. Future trials should test whether reducing serum phosphate improves renal outcomes and optimizes the renoprotective effect of ACE inhibition.

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Section: Discussionmentioning

confidence: 99%

Phosphate May Promote CKD Progression and Attenuate Renoprotective Effect of ACE Inhibition

Zoccali

Ruggenenti

Perna

et al. 2011

Journal of the American Society of Nephrology

195

131

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“…Direct effect(s) of RAS components on 1␣-hydroxylase or VDR have not been found; however, ANG II reduces renal KLOTHO expression (286,348,443,453), which interferes with FGF23 signaling and results in elevated FGF23 levels (reviewed in Ref. 97).…”

Section: The Klotho-vitamin D-ras Connectionmentioning

confidence: 99%

Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition

Cavanagh

Inserra

Ferder

2015

American Journal of Physiology-Heart and Circulatory Physiology

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de Cavanagh EM, Inserra F, Ferder L. Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition. Am J Physiol Heart Circ Physiol 309: H15-H44, 2015. First published May 1, 2015; doi:10.1152/ajpheart.00459.2014, renin angiotensin system blockade (RAS-bl), and rapamycin-mediated mechanistic target of rapamycin (mTOR) inhibition increase survival and retard aging across species. Previously, we have summarized CR and RAS-bl's converging effects, and the mitochondrial function changes associated with their physiological benefits. mTOR inhibition and enhanced sirtuin and KLOTHO signaling contribute to the benefits of CR in aging. mTORC1/mTORC2 complexes contribute to cell growth and metabolic regulation. Prolonged mTORC1 activation may lead to age-related disease progression; thus, rapamycin-mediated mTOR inhibition and CR may extend lifespan and retard aging through mTORC1 interference. Sirtuins by deacetylating histone and transcription-related proteins modulate signaling and survival pathways and mitochondrial functioning. CR regulates several mammalian sirtuins favoring their role in aging regulation. KLOTHO/fibroblast growth factor 23 (FGF23) contribute to control Ca 2ϩ , phosphate, and vitamin D metabolism, and their dysregulation may participate in age-related disease. Here we review how mTOR inhibition extends lifespan, how KLOTHO functions as an aging suppressor, how sirtuins mediate longevity, how vitamin D loss may contribute to age-related disease, and how they relate to mitochondrial function. Also, we discuss how RAS-bl downregulates mTOR and upregulates KLOTHO, sirtuin, and vitamin D receptor expression, suggesting that at least some of RAS-bl benefits in aging are mediated through the modulation of mTOR, KLOTHO, and sirtuin expression and vitamin D signaling, paralleling CR actions in age retardation. Concluding, the available evidence endorses the idea that RAS-bl is among the interventions that may turn out to provide relief to the spreading issue of age-associated chronic disease. mechanistic target of rapamycin; vitamin D; caloric restriction; renin-angiotensin system EFFORTS AIMED AT DECIPHERING the mechanisms that underlie the aging process have unveiled three interventions that can increase survival and retard age-related diseases from lower organisms to mammals, i.e., caloric restriction (CR) (84,85,140,160,334), mechanistic target of rapamycin (mTOR; originally mammalian TOR) inhibition by rapamycin (173,196,281), and renin-angiotensin system blockade (RAS-bl) (20, 21, 26,63,253,284,354), although the latter has been less studied. In light of these findings, some intriguing questions come to mind: Do these interventions attenuate aging by interfering with common mechanisms? Do the mechanisms that are interfered with by CR, rapamycin, and RAS-bl mutually affect each other? Are there any pathways involved exclusively with a certain intervention?Previously (101), we have discussed the converging effects d...

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“…Renal 1,25(OH) 2 D depletion may also potentiate a-klotho deficiency through activation of the renin-angiotensin system and generation of angiotensin II (121). Interestingly, several reports of renin-angiotensin system inhibition in rodent CKD models suggest that such interventions may have beneficial effects on the FGF23-klotho axis by restoring renal a-klotho expression (122) and augmenting phosphate excretion while moderating the increase in systemic FGF23 levels with disease progression (87). Likewise, in CKD mice, VDRAs were found to increase soluble klotho levels in the serum and urine (but not the kidney), increase phosphaturia, and lower serum FGF23 concentration (123).…”

Section: Vitamin Dmentioning

confidence: 99%

The Use of Fibroblast Growth Factor 23 Testing in Patients with Kidney Disease

Smith

2014

Clinical Journal of the American Society of Nephrology

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The emergence of fibroblast growth factor 23 as a potentially modifiable risk factor in CKD has led to growing interest in its measurement as a tool to assess patient risk and target therapy. This review discusses the analytical and clinical challenges faced in translating fibroblast growth factor 23 testing into routine practice. As for other bone mineral markers, agreement between commercial fibroblast growth factor 23 assays is poor, mainly because of differences in calibration, but also, these differences reflect the variable detection of hormone fragments. Direct comparison of readout from different assays is consequently limited and likely hampers setting uniform fibroblast growth factor 23-directed targets. Efforts are needed to standardize assay output to enhance clinical use. Fibroblast growth factor 23 is robustly associated with cardiovascular and renal outcomes in patients with CKD and adds value to risk assessments based on conventional risk factors. Compared with most other mineral markers, fibroblast growth factor 23 shows better intraindividual temporal stability, with minimal diurnal and week-to-week variability, but substantial interindividual variation, maximizing discriminative power for risk stratification. Conventional therapeutic interventions for the CKD-mineral bone disorder, such as dietary phosphate restriction and use of oral phosphate binders or calcimimetics, are associated with variable efficacy at modulating circulating fibroblast growth factor 23 concentrations, like they are for other mineral metabolites. Dual therapy with dietary phosphate restriction and noncalcium-based binder use achieves the most consistent fibroblast growth factor 23-lowering effect and seems best monitored using an intact assay. Additional studies are needed to evaluate whether strategies aimed at reducing levels or antagonizing its action have beneficial effects on clinical outcomes in CKD patients. Moreover, a better understanding of the mechanisms driving fibroblast growth factor 23 elevations in CKD is needed to inform the use of therapeutic interventions targeting fibroblast growth factor 23 excess. This evidence must be forthcoming to support the use of fibroblast growth factor 23 measurement and fibroblast growth factor 23-directed therapy in the clinic.

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Angiotensin II blockade upregulates the expression of Klotho, the anti-ageing gene, in an experimental model of chronic cyclosporine nephropathy

Abstract: Angiotensin II may play a pivotal role in regulating Klotho expression in CsA-induced renal injury. AT1 receptor blocker may inhibit the ageing process by decreasing oxidative stress caused by CsA.

Cited by 158 publications

References 58 publications

Phosphate May Promote CKD Progression and Attenuate Renoprotective Effect of ACE Inhibition

Phosphate May Promote CKD Progression and Attenuate Renoprotective Effect of ACE Inhibition

Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition

The Use of Fibroblast Growth Factor 23 Testing in Patients with Kidney Disease

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