Klotho upregulation by rapamycin protects against vascular disease in CKD

Hamano, Takayuki

doi:10.1038/ki.2015.223

Cited by 17 publications

(11 citation statements)

References 10 publications

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“…36,37 Klotho-deficient mice show low bone formation and resorption activities, which result in osteopenia, indicating that Klotho can directly affect bone formation and remodeling. 4 Impressively, rhein treatment effectively alleviated disturbed serum and uric biochemistry, serum FGF-23, and intact PTH and attenuated renal and bone injuries in a Klotho-dependent manner, consistent with previous observations that Klotho-targeted strategies with chemical agents such as rapamycin, resveratrol, and testosterone remarkably protected against kidney and kidney damage-associated vascular calcifications via upregulating Klotho, [38][39][40][41] indicating that rhein reversal of Klotho loss contributes significantly to its renal and bone protective functions. The molecular events that lead to Klotho deficiency after kidney injuries are not fully understood.…”

Section: Rhein Derepression Of Klotho Protects Against Renal Damage Isupporting

confidence: 87%

Rhein reverses Klotho repression via promoter demethylation and protects against kidney and bone injuries in mice with chronic kidney disease

Zhang

Liu

Lin

et al. 2017

Kidney International

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Rhein is an anthraquinone compound isolated from the medicinal plant rhubarb and mainly used in the clinical treatment of diabetic nephropathy. Rhein exhibits various renoprotective functions, but the underlying mechanisms are not fully determined. However, its renoprotective properties recapitulate the role of Klotho, a renal-specific antiaging protein critical for maintaining kidney homeostasis. Here we explored the connections between rhein renoprotection and Klotho in a mouse model of adenine-induced chronic kidney disease. In addition to being an impressive Klotho upregulator, rhein remarkably reversed renal Klotho deficiency in adenine-treated mice. This effect was associated with significant improvement in disturbed serum biochemistry, profibrogenic protein expression, and kidney and bone damage. Further investigation of the molecular basis of Klotho loss revealed that these kidneys displayed marked inductions of DNA methyltransferase DNMT1/DNMT3a and Klotho promoter hypermethylation, whereas rhein treatment effectively corrected these alterations. The renal protective effects of rhein were largely abolished when Klotho was knocked-down by RNA interferences, suggesting that rhein reversal of Klotho deficiency is essential for its renoprotective actions. Thus, our study clarifies how rhein regulation of Klotho expression contributes to its renoprotection and brings new insights into Klotho-targeted strategy for the treatment of kidney diseases of various etiologies.

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Section: Rhein Derepression Of Klotho Protects Against Renal Damage Isupporting

confidence: 87%

Rhein reverses Klotho repression via promoter demethylation and protects against kidney and bone injuries in mice with chronic kidney disease

Zhang

Liu

Lin

et al. 2017

Kidney International

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“…Zhang et al reported that cleaved klotho protein attenuates the Phosphate-induced human bone marrow mesenchymal stem cells differentiation into osteoblast-like cells in vitro via inactivation of the FGFR1/ERK signalling pathway [ 95 ]. In addition, the up-regulation of klotho expression by the inhibition of rapamycin signalling also ameliorates VC and protects against vascular disease in CKD [ 96 , 97 ]. Another study showed that Intermedin 1-53 attenuates VC in rats with CKD by up-regulating membrane-bound klotho expression in the vessel wall [ 98 ].…”

Section: Main Textmentioning

confidence: 99%

The role of klotho in chronic kidney disease

et al. 2018

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Chronic kidney disease (CKD) is an inherently systemic disease that refers to a long-term loss of kidney function. The progression of CKD has repercussions for other organs, leading to many kinds of extrarenal complications. Intensive studies are now being undertaken to reveal the risk factors and pathophysiological mechanism of this disease. During the past 20 years, increasing evidence from clinical and basic studies has indicated that klotho, which was initially known as an anti-aging gene and is mainly expressed in the kidney, is significantly correlated with the development and progression of CKD and its complications. Here, we discuss in detail the role and pathophysiological implications of klotho in ion disorders, the inflammation response, vascular calcification, mineral bone disorders, and renal fibrosis in CKD. Based on the pathogenic mechanism of klotho deficiency and klotho decline in urine early in CKD stage 2 and even earlier in CKD stage 1, it is not difficult to understand that soluble klotho can serve as an early and sensitive marker of CKD. Moreover, the prevention of klotho decline by several mechanisms can attenuate renal injuries, retard CKD progression, ameliorate extrarenal complications, and improve renal function. In this review, we focus on the functions and pathophysiological implications of klotho in CKD and its extrarenal complications as well as its potential applications as a diagnostic and/or prognostic biomarker for CKD and as a novel treatment strategy to improve and decrease the burden of comorbidity in CKD.

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“…It has been reported that immunosuppressive protocols might modulate Klotho expression [7,10,11]. Zhao et al [7] showed activation of mTOR signaling in a rat model of chronic renal failure.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the Mammalian Target of Rapamycin May Augment the Increase in Soluble Klotho Levels in Renal Transplantation Recipients

et al. 2019

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Background/Aims: α-Klotho is mainly expressed in the kidneys, and its soluble form can prevent vascular calcifications. Inhibition of the mammalian target of rapamycin (mTOR) upregulates Klotho. We assessed serial changes in the levels of soluble Klotho (sKlotho) in recipients before and after renal transplantation and investigated the effects of an mTOR inhibitor. Methods: Serum sKlotho levels were measured in 36 recipients before and 1 year after transplantation and compared between those taking everolimus and those not taking everolimus. Results: sKlotho levels were higher after transplantation than before transplantation (369.3 vs. 211.8 pg/mL). After transplantation, sKlotho levels were significantly higher in recipients taking everolimus than in those not taking everolimus (536.7 vs. 332.4 pg/mL). Conclusion: Our results suggest that mTOR inhibition may augment the increase in sKlotho levels in transplant recipients. Further studies are needed to examine whether mTOR inhibitors suppress the development of vascular complications via upregulation of Klotho expression in renal transplant recipients.

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Klotho upregulation by rapamycin protects against vascular disease in CKD

Cited by 17 publications

References 10 publications

Rhein reverses Klotho repression via promoter demethylation and protects against kidney and bone injuries in mice with chronic kidney disease

Rhein reverses Klotho repression via promoter demethylation and protects against kidney and bone injuries in mice with chronic kidney disease

The role of klotho in chronic kidney disease

Inhibition of the Mammalian Target of Rapamycin May Augment the Increase in Soluble Klotho Levels in Renal Transplantation Recipients

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