Xeno-Klotho Inhibits Parathyroid Hormone Signaling

Takenaka, Tsuneo; Inoue, Tsutomu; Miyazaki, Takashi; Hayashi, Matsuhiko; Suzuki, Hiromichi

doi:10.1002/jbmr.2691

Cited by 31 publications

(33 citation statements)

References 32 publications

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“…As detailed previously, 8 antibodies against the human AT1R (10 μg; Abcam) were incubated with protein G-Sepharose beads (25% v/v; GE Health Care Life Sciences) in 0.1 mL binding buffer (Krebs- Ringer-Hepes buffer with 1% BSA) for 2 hours at room temperature. After washing the beads with the binding buffer, full-length human AT1R (1 μΜ; Novus Biologicals) was added to the beads suspended in 0.1 mL binding buffer, and the beads were incubated further at 4°C for 15 hours.…”

Section: Methodsmentioning

confidence: 99%

“…8 Next, the beads were washed 3× with the binding buffer and 3× with the Krebs-Ringer-Hepes buffer lacking BSA and were subjected to a scintillation counter. Nonspecific binding was determined by replacing rh-klotho with unlabeled Ang II (Sigma-Aldrich) in an excess of 100-fold 125 I-Ang II.…”

Section: Methodsmentioning

confidence: 99%

“…Because variations in intracellular IP3 levels are relatively large among cultured sheets, the medium was used as a sample. 8 …”

Section: Methodsmentioning

confidence: 99%

“…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). 1,4,8,9 …”

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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: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Because variations in intracellular IP3 levels are relatively large among cultured sheets, the medium was used as a sample. 8 …”

Section: Methodsmentioning

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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“…Intraperitoneal administration of Klotho protein to Klotho-deficient mice extended lifespan and attenuated systemic calcification and renal fibrosis; the protective effect on renal function was via downregulation of renal TGF-b mRNA expression, a main regulator of renal fibrosis (135). In addition, Takenaka et al (136) recently showed that exogenous or xeno-Klotho directly interacts with the PTH receptor to inhibit PTH signaling. Moreover, xeno-Klotho inhibited the PTH-induced expression of renal 1a-hydroxylase both in vitro and in vivo, indicating that Klotho may act as a second messenger for FGF23 in its inhibition of vitamin D. Although these results in animals are exciting, more research is needed to determine if soluble Klotho replacement and/or upregulation of membrane-bound Klotho will provide beneficial therapy for renal and cardiovascular dysfunction in patients with CKD.…”

Section: Indirect Approachesmentioning

confidence: 99%

Phosphate Toxicity in CKD: The Killer among Us

Ritter¹,

Slatopolsky²

2016

CJASN

109

111

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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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Mechanisms and Regulation of Intestinal Phosphate Absorption

Hernando¹,

Wagner²

2018

Comprehensive Physiology

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States of hypo- and hyperphosphatemia have deleterious consequences including rickets/osteomalacia and renal/cardiovascular disease, respectively. Therefore, the maintenance of appropriate plasma levels of phosphate is an essential requirement for health. This control is executed by the collaborative action of intestine and kidney whose capacities to (re)absorb phosphate are regulated by a number of hormonal and metabolic factors, among them parathyroid hormone, fibroblast growth factor 23, 1,25(OH) vitamin D , and dietary phosphate. The molecular mechanisms responsible for the transepithelial transport of phosphate across enterocytes are only partially understood. Indeed, whereas renal reabsorption entirely relies on well-characterized active transport mechanisms of phosphate across the renal proximal epithelia, intestinal absorption proceeds via active and passive mechanisms, with the molecular identity of the passive component still unknown. The active absorption of phosphate depends mostly on the activity and expression of the sodium-dependent phosphate cotransporter NaPi-IIb (SLC34A2), which is highly regulated by many of the factors, mentioned earlier. Physiologically, the contribution of NaPi-IIb to the maintenance of phosphate balance appears to be mostly relevant during periods of low phosphate availability. Therefore, its role in individuals living in industrialized societies with high phosphate intake is probably less relevant. Importantly, small increases in plasma phosphate, even within normal range, associate with higher risk of cardiovascular disease. Therefore, therapeutic approaches to treat hyperphosphatemia, including dietary phosphate restriction and phosphate binders, aim at reducing intestinal absorption. Here we review the current state of research in the field. © 2017 American Physiological Society. Compr Physiol 8:1065-1090, 2018.

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Xeno-Klotho Inhibits Parathyroid Hormone Signaling

Cited by 31 publications

References 32 publications

Klotho Ameliorates Medullary Fibrosis and Pressure Natriuresis in Hypertensive Rat Kidneys

Klotho Ameliorates Medullary Fibrosis and Pressure Natriuresis in Hypertensive Rat Kidneys

Phosphate Toxicity in CKD: The Killer among Us

Mechanisms and Regulation of Intestinal Phosphate Absorption

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