Klotho suppresses the renin-angiotensin system in adriamycin nephropathy

Takenaka, Tsuneo; Inoue, Tsutomu; Mizutani, Takashi; Kobori, Hiroyuki; Nishiyama, Akira; Ishii, Naohito; Hayashi, Matsuhiko; Suzuki, Hiromichi

doi:10.1093/ndt/gfw340

Cited by 26 publications

(40 citation statements)

References 54 publications

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“…32 The excretion of PGF2α represents an index of oxidative stress. 6,7 Thus, these findings suggested that klotho-induced decrease in renal Ang II levels and oxidative stress contributed to the decrements of HIF-1α abundance. Wang et al 15 showed that Ang II induced profibrotic changes by activating HIF-1α in medullary fibroblasts.…”

Section: Discussionmentioning

confidence: 80%

“…Klotho protein supplementation substantially increased renal klotho expression (Figure 4D) and elevated both serum klotho levels and urinary klotho excretion (Figure 4E and 4F) to the levels similar to normotensive control rats. 6 Of note, klotho supplementation failed to alter serum calcium, phosphate, and FGF23 levels in this model (Table S2). Early phase of kidney disease model may relate to small effects of klotho supplementation on mineral metabolism.…”

Section: Resultsmentioning

confidence: 87%

“…We recently showed that GSK3ß (glycogen synthase kinase 3β) inhibition increased AGT expression in the kidneys. 6 GSK3ß is activated by the Akt pathway to control glucose metabolism. Collectively, the present findings suggested that klotho- induced modulations of renal RAS involve multiple pathways, AT1R internalization, as well as Akt phosphorylation and oxidative stress in hypertensive kidneys.…”

Section: Discussionmentioning

confidence: 99%

“…Hypertensive kidneys show weak TGFß and Snail levels compared with kidneys with adriamycin nephropathy. 6 Albuminuria strongly induces TGFß expression in tubular cells of the nephron. 29 However, albumin excretion in uninephrectomized SHRs was much lower than that in rats with adriamycin nephropathy.…”

Section: Discussionmentioning

confidence: 99%

“…4 Secreted klotho binds to Wnt, thus inhibiting Wnt signaling, which promotes aging and activates the renin-Ang (angiotensin) system (RAS). 5,6 Both renal and circulating klotho levels are decreased in hypertensive nephrosclerosis. 7 Klotho interacts with many membrane proteins, such as transient receptor potential channel 1, transient receptor potential vanilloid 5, type2 sodium-phosphate co-transporter, and receptors of fibroblast growth factor 23, IGF (insulin-like growth factor), parathyroid hormone, and TGFß (transforming growth factor β).…”

mentioning

confidence: 99%

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Klotho Ameliorates Medullary Fibrosis and Pressure Natriuresis in Hypertensive Rat Kidneys

et al. 2018

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Renal expression of klotho is reduced in hypertension. Experiments were performed to examine whether exogenous klotho protein supplementation ameliorates pressure natriuresis in early phase of hypertension, using stroke-prone spontaneously hypertensive rats (sp-SHR). The interactions between klotho protein and renal renin-Ang (angiotensin) system were examined with immunoprecipitation and cell culture methods. Uninephrectomy was performed in sp-SHRs to induce nephrosclerosis, and they were treated with exogenous klotho protein or vehicle. Exogenous klotho protein supplementation to sp-SHR decreased blood pressure, renal Ang II levels, AGT (angiotensinogen) expression, HIF (hypoxia-inducible factor)-1α abundance, and medullary fibronectin levels, with increased renal klotho expression and serum and urine klotho levels. Klotho supplementation also reduced kidney weight, renal phosphorylated Akt, and mTOR (mammalian target of rapamycin) abundance. Furthermore, klotho supplementation restored renal autoregulation of glomerular filtration rate and enhanced pressure-induced natriuresis in sp-SHR. Klotho protein bound to AT1R (Ang II type- 1 receptor) and decreased the presence of AT1R on HK-2 (human proximal tubular) cells, attenuating inositol triphosphate generation. Klotho protein suppressed Ang II-induced increments of AGT expression in HK-2 cells. Collectively, the present data demonstrate that klotho binds with the AT1R to suppress Ang signal transduction, participating in inactivating renal renin-Ang system. Our results also suggest that exogenous klotho supplementation represses Akt-mTOR signaling to reduce renal hypertrophy and restore the autoregulatory ability of glomerular filtration rate in uninephrectomized sp- SHRs. Finally, the present findings implicate that klotho supplementation inhibits HIF-1α pathway and medullary fibrosis, contributing to enhancements of pressure natriuresis and reduction in blood pressure.

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Section: Discussionmentioning

confidence: 80%

Section: Resultsmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Klotho Ameliorates Medullary Fibrosis and Pressure Natriuresis in Hypertensive Rat Kidneys

et al. 2018

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αKlotho–FGF23 interactions and their role in kidney disease: a molecular insight

Smith

Holt

Hewitson

2019

Cell. Mol. Life Sci.

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Following the serendipitous discovery of the ageing suppressor, αKlotho (αKl), several decades ago, a growing body of evidence has defined a pivotal role for its various forms in multiple aspects of vertebrate physiology and pathology. The transmembrane form of αKl serves as a co-receptor for the osteocyte-derived mineral regulator, fibroblast growth factor (FGF)23, principally in the renal tubules. However, compelling data also suggest that circulating soluble forms of αKl, derived from the same source, may have independent homeostatic functions either as a hormone, glycan-cleaving enzyme or lectin. Chronic kidney disease (CKD) is of particular interest as disruption of the FGF23–αKl axis is an early and common feature of disease manifesting in markedly deficient αKl expression, but FGF23 excess. Here we critically discuss recent findings in αKl biology that conflict with the view that soluble αKl has substantive functions independent of FGF23 signalling. Although the issue of whether soluble αKl can act without FGF23 has yet to be resolved, we explore the potential significance of these contrary findings in the context of CKD and highlight how this endocrine pathway represents a promising target for novel anti-ageing therapeutics.

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DL-3-n-butylphthalide attenuates doxorubicin-induced acute cardiotoxicity via Nrf2/HO-1 signaling pathway

Li,

Zhang,

et al. 2024

Heliyon

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Klotho suppresses the renin-angiotensin system in adriamycin nephropathy

Cited by 26 publications

References 54 publications

Klotho Ameliorates Medullary Fibrosis and Pressure Natriuresis in Hypertensive Rat Kidneys

Klotho Ameliorates Medullary Fibrosis and Pressure Natriuresis in Hypertensive Rat Kidneys

αKlotho–FGF23 interactions and their role in kidney disease: a molecular insight

DL-3-n-butylphthalide attenuates doxorubicin-induced acute cardiotoxicity via Nrf2/HO-1 signaling pathway

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