Severely Reduced Production of Klotho in Human Chronic Renal Failure Kidney

Koh, Naoki; Fujimori, Toshihiko; Nishiguchi, Shuhei; Tamori, Akihiro; Shiomi, Susumu; Nakatani, Tatsuya; Sugimura, Kazunobu; Kishimoto, Toshifumi; Kinoshita, Shigeyoshi; Kuroki, Tetsuo; Nabeshima, Yo‐ichi

doi:10.1006/bbrc.2000.4226

Cited by 437 publications

(315 citation statements)

References 23 publications

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“…Indeed, α‐Klotho deficiency in mice leads to a limited vasodilatory response and increased permeability in the endothelial cells among other vascular complications also observed in CKD patients 22, 23, 24, 41. As reported previously in other uremic in vivo models20, 21 and CKD patients,42, 43 we confirmed that impaired kidney function induced downregulation of mRNA and α‐Klotho protein levels in kidney tissue accompanied by lower serum concentrations. However, it was unexpected that neither vitamin D deficiency nor paricalcitol supplementation affected α‐Klotho in the kidney tissue or its concentration in serum.…”

Section: Discussionsupporting

confidence: 89%

Vitamin D Attenuates Endothelial Dysfunction in Uremic Rats and Maintains Human Endothelial Stability

Cuenca

Ferrantelli

Meinster

et al. 2018

JAHA

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BackgroundDysfunctional endothelium may contribute to the development of cardiovascular complications in chronic kidney disease (CKD). Supplementation with active vitamin D has been proposed to have vasoprotective potential in CKD, not only by direct effects on the endothelium but also by an increment of α‐Klotho. Here, we explored the capacity of the active vitamin D analogue paricalcitol to protect against uremia‐induced endothelial damage and the extent to which this was dependent on increased α‐Klotho concentrations.Methods and ResultsIn a combined rat model of CKD with vitamin D deficiency, renal failure induced vascular permeability and endothelial‐gap formation in thoracic aorta irrespective of baseline vitamin D, and this was attenuated by paricalcitol. Downregulation of renal and serum α‐Klotho was found in the CKD model, which was not restored by paricalcitol. By measuring the real‐time changes of the human endothelial barrier function, we found that paricalcitol effectively improved the recovery of endothelial integrity following the addition of the pro‐permeability factor thrombin and the induction of a wound. Furthermore, immunofluorescence staining revealed that paricalcitol promoted vascular endothelial‐cadherin–based cell‐cell junctions and diminished F‐actin stress fiber organization, preventing the formation of endothelial intracellular gaps.ConclusionsOur results demonstrate that paricalcitol attenuates the CKD‐induced endothelial damage in the thoracic aorta and directly mediates endothelial stability in vitro by enforcing cell‐cell interactions.

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Section: Discussionsupporting

confidence: 89%

Vitamin D Attenuates Endothelial Dysfunction in Uremic Rats and Maintains Human Endothelial Stability

Cuenca

Ferrantelli

Meinster

et al. 2018

JAHA

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“…31 Renal klotho expression was found to decrease in spontaneously hypertensive rats, 5/6 nephrectomized rats, noninsulin-dependent diabetes mellitus rats and in ischemia-reperfusion injury models. 32 In humans, klotho expression also decreases in CKD patients, 33 and also has protective renal effects by protecting cells/ tissues from oxidative stress and apoptosis. 29 In our study, we demonstrated that direct renin inhibition significantly increased klotho expression in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

Aliskiren reduced renal fibrosis in mice with chronic ischemic kidney injury—beyond the direct renin inhibition

et al. 2011

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Chronic renal ischemia leads to renal fibrosis and atrophy. Activation of the renin-angiotensin-aldosterone system is one of the main mechanisms driving chronic renal ischemic injury. The aim of the present study was to define the effect of aliskiren in chronic ischemia of the kidney. Two-kidney, one-clip mice were used to study chronic renal ischemia. Aliskiren significantly lowered the blood pressure in mice with renal artery constriction (92.1±1.1 vs. 81.0±1.8 mm Hg, Po0.05). Renin expression was significantly increased in ischemic kidneys when treated with aliskiren. In addition, (Pro)renin receptor expression was decreased by aliskiren in ischemic kidneys. Aliskiren treatment significantly increased klotho expression and reduced the expression of fibrogenic cystokines, caspase-3 and Bax in ischemic kidneys. Histological examination revealed that aliskiren significantly reduced the nephrosclerosis score (4.5±1.9 vs. 7.3±0.4, Po0.05). Immunofluorescence staining also showed that aliskiren decreased the deposition of interstitial collagen I in ischemic kidneys. In conclusion, direct renin inhibition significantly reduced renal fibrosis and apoptosis following chronic renal ischemia.

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“…Genetic variants of Klotho have been associated with human ageing [2], and a loss of function mutation has been described in a patient with high blood phosphate levels and soft tissue and vascular calcification [3]. Klotho is predominantly expressed in the kidneys and choroid plexus, and expression decreases with chronic renal failure [4]. Klotho protein exists in membrane-bound and secreted soluble forms.…”

Section: Introductionmentioning

confidence: 99%

Excessively high soluble Klotho in patients with acromegaly

Sze

Bernays

Zwimpfer³

et al. 2012

Journal of Internal Medicine

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Objectives. Klotho-deficient mice develop a syndrome resembling accelerated ageing, and genetic variants of Klotho have been associated with human ageing. In humans, serum levels of soluble Klotho decrease with age and with chronic renal failure. The aim of our study was to examine the relationship between excess growth hormone (GH) and serum levels of Klotho in patients with acromegaly, a disease usually caused by a pituitary adenoma, which is associated with high phosphate levels and reduced life expectancy.Patients and design. We determined the levels of soluble Klotho, GH and insulin-like growth factor 1 (IGF-1) in serum samples from 24 consecutive patients with acromegaly (nine women ⁄ 15 men, age 28-76 years) before and after transsphenoidal surgery.Results. Soluble Klotho levels were excessively high at baseline (mean ± SEM, 4.2 ± 0.7 ng mL )1 ) and correlated with GH (r = 0.64), IGF-1 (r = 0.57) and tumour size (r = 0.5). In multiple regression analysis, soluble Klotho was associated with GH after correction for age, gender and levels of creatinine and phosphate (P = 0.029). After surgery, GH and IGF-1 levels decreased in all patients (from 26.3 ± 5.2 to 2.6 ± 0.6 lg L )1 , P < 0.0001, and from 588 ± 35 to 193 ± 12 lg L )1 , P < 0.001, 0.0001, respectively). Creatinine increased from 71 ± 3 to 80 ± 3 lmol L )1 (P < 0.001), and phosphate decreased from 1.37 ± 0.04 to 1.06 ± 0.02 mmol L )1 (P < 0.001). The markedly increased preoperative levels of soluble Klotho returned towards normal after surgery (0.7 ± 0.1 ng mL )1 , P < 0.0001).Conclusions. This is the first study to show dramatically increased soluble Klotho levels in an acquired disease in humans. Reversal following tumour removal suggests a causal relation between the GH-producing adenoma and high serum Klotho concentration in acromegaly.

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Severely Reduced Production of Klotho in Human Chronic Renal Failure Kidney

Cited by 437 publications

References 23 publications

Vitamin D Attenuates Endothelial Dysfunction in Uremic Rats and Maintains Human Endothelial Stability

Vitamin D Attenuates Endothelial Dysfunction in Uremic Rats and Maintains Human Endothelial Stability

Aliskiren reduced renal fibrosis in mice with chronic ischemic kidney injury—beyond the direct renin inhibition

Excessively high soluble Klotho in patients with acromegaly

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