Differential expression and regulation of Klotho by paricalcitol in the kidney, parathyroid, and aorta of uremic rats

Ritter, Cynthia S.; Zhang, Sarah; Delmez, James A.; Finch, Jane; Slatopolsky, Eduardo

doi:10.1038/ki.2015.22

Cited by 60 publications

(47 citation statements)

References 72 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%

“…Instead of a direct effect on target tissue, as an alternative explanation for beneficial effects of active vitamin D, it has been postulated that it can upregulate renal α‐Klotho as the actual effector of remote beneficial effects, after shedding its ectodomain 20, 21, 39, 40. 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.…”

Section: Discussionmentioning

confidence: 99%

“…A small number of prior studies have suggested benefits of the active vitamin D analogue paricalcitol on endothelial stability in animal models of CKD16, 17 and even in patients 18, 19. Interestingly, paricalcitol supplementation increased kidney and serum α‐Klotho levels in in vivo models of CKD 20, 21. α‐Klotho is an antiaging protein, and its deficiency is associated with a cardiovascular phenotype including arteriosclerosis, vascular calcification, and, importantly, endothelial cell dysfunction 22, 23.…”

Section: Introductionmentioning

confidence: 99%

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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%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Cuenca

Ferrantelli

Meinster

et al. 2018

JAHA

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“…In advanced CKD, FGF23 resistance is attributed to the reduced expression of the parathyroid Klotho-FGFR1 receptor complex in the kidney, PTG, and aorta (59,66,71). Reduced concentrations of renal and soluble Klotho are found in mice with experimentally induced CKD (72), and our laboratory recently reported that renal Klotho expression is drastically reduced in uremic rats (57). As well, reduced renal and soluble Klotho levels are found in patients with CKD (73,74).…”

Section: Phosphate and Ckdmentioning

confidence: 99%

Phosphate Toxicity in CKD: The Killer among Us

Ritter¹,

Slatopolsky²

2016

CJASN

Self Cite

121

113

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Maintenance of a normal serum phosphate level depends on absorption in the gut, reabsorption and excretion by the kidney, and the flux between the extracellular and skeletal pools. Phosphate homeostasis is a coordinated, complex system of crosstalk between the bone, intestine, kidney, and parathyroid gland. Dysfunction of this system has serious clinical consequences in healthy individuals and those with conditions, such as CKD, in which hyperphosphatemia is associated with increased risks of cardiovascular morbidity and mortality. The last halfcentury of renal research has helped define the contribution of the parathyroid hormone, calcitriol, fibroblast growth factor 23, and Klotho in the regulation of phosphate. However, despite new discoveries and insights gained during this time, what remains unchanged is the recognition that phosphate retention is the initiating factor for the development of many of the complications observed in CKD, namely secondary hyperparathyroidism and bone and cardiovascular diseases. Controlling phosphate load remains the primary goal in the treatment of CKD. This review discusses the clinical effects of dysregulated phosphate metabolism, particularly in CKD, and its association with cardiovascular disease. The importance of early control of phosphate load in the treatment of CKD is emphasized, and the latest research in the treatment of phosphate retention is discussed.

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“…Paricalcitol treatment of uremic mice restores deficient Klotho synthesis in CKD renal tissue [162] . …”

Section: Novel Therapeutic Interventionsmentioning

confidence: 98%

Stop chronic kidney disease progression: Time is approaching

Din¹,

Salem²,

Abdulazim³

2016

WJN

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Progression of chronic kidney disease (CKD) is inevitable. However, the last decade has witnessed tremendous achievements in this field. Today we are optimistic; the dream of withholding this progression is about to be realistic. The recent discoveries in the field of CKD management involved most of the individual diseases leading the patients to end-stage renal disease. Most of these advances involved patients suffering diabetic kidney disease, chronic glomerulonephritis, polycystic kidney disease, renal amyloidosis and chronic tubulointerstitial disease. The chronic systemic inflammatory status and increased oxidative stress were also investigated. This inflammatory status influences the antisenescence Klotho gene expression. The role of Klotho in CKD progression together with its therapeutic value are explored. The role of gut as a major source of inflammation, the pathogenesis of intestinal mucosal barrier damage, the role of intestinal alkaline phosphatase and the dietary and therapeutic implications add a novel therapeutic tool to delay CKD progression.

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Differential expression and regulation of Klotho by paricalcitol in the kidney, parathyroid, and aorta of uremic rats

Cited by 60 publications

References 72 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

Phosphate Toxicity in CKD: The Killer among Us

Stop chronic kidney disease progression: Time is approaching

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