- Leucine rich repeat-containing protein (LRG)
- Osteopontin focus
- Angiotensinogen: analyzing the key precursor of angiotensin
- Oncogene research focus
- mTOR in aging and cancer
- Alpha-Klotho focus
- Detecting and analyzing tyrosine kinase proteins
- Osteocalcin focus
- Detecting and analyzing Alzheimer's Disease targets
Alpha-Klotho: a regulator of metabolic processes
Role of alpha-Klotho in chronic kidney disease, metabolism, and aging
Alpha-Klotho is an approximately 130-kDa type I membrane protein that contains a short intracellular domain and two internal repeat regions (hKL1 and hKL2 in humans, and mKL1 and mKL2 in mice) in its larger extracellular domain. We offer a sensitive alpha-Klotho ELISA kit to study this protein target, which has been found to play a role in:
- Chronic kidney disease (CKD)
- Metabolism and calcium homeostasis
- Cardiovascular disease
- Immunology and inflammation
Learn more about using our alpha-Klotho assay kit.
Expression of alpha-Klotho
Alpha-Klotho is preferentially expressed in parathyroid glands, the kidney distal convoluted tubules, and the brain choroid plexus (Manya et al. 2010). A soluble form of alpha-Klotho is generated when the extracellular domain of membrane-bound alpha-Klotho is shed and released into the circulation. Alternate splicing can also account for soluble alpha-Klotho. The alpha-Klotho protein has a global effect on organ health and function: mice lacking the klotho gene (kl/kl) show accelerated aging and numerous disease states, including osteoporosis, arteriosclerosis, skin atrophy, emphysema, pituitary gland abnormalities, Purkinje cell decrease and Parkinsonian gait, and atrophy of the genital organs and thymus (Kuro-o et al. 1997).
Because alpha-Klotho is involved in many organ systems, it is hypothesized that the protein is involved in fundamental metabolic processes. Consistent with this prediction, in homozygous kl/kl mice blood glucose and insulin levels were significantly lower, and insulin sensitivity was much higher compared to wild-type mice (Utsugi et al. 2000). In addition, soluble alpha-Klotho helps regulate mineral metabolism, including circulating calcium and inorganic phosphate homeostasis (Yamazaki et al. 2010). Manya et al. describe four alpha-Klotho-mediated pathways, including calcium channel activity, insulin/IGF signal inhibition, FGFR1(IIIc) binding and conversion to the FGF23 receptor, and alpha1-Na+/K+-ATPase binding and recruitment of the Na+/K+-ATPase complex. Two of these Klotho pathways are illustrated below.
The human soluble alpha-Klotho assay (Cat. # 27998A) uses a monoclonal antibody that has strong affinity and specificity for the tertiary protein structure of the alpha-Klotho extracellular domain. The antibodies and substrates of the alpha-Klotho ELISA were developed by Yamazaki and colleagues (Yamazaki et al. 2010). This alpha-Klotho ELISA can be used to accurately detect and measure circulating human alpha-Klotho levels.
Our alpha-Klotho assay kit was compared with other commercially available kits for the measurement of alpha-Klotho in serum and plasma of patients with chronic kidney disease. In this experiment, the within- and between-run variations of the assay were <5% and <8%, respectively (Heijboer et al. 2013). These values were far better than the within-run variations of 32% and 13% noted for alpha-Klotho assays purchased from Companies U and C, respectively.
This alpha-Klotho assay kit has been used extensively to study the disease states and processes listed below.
Chronic kidney disease (CKD)
- Alpha-Klotho levels may be a useful indicator of kidney damage (Pavik et al. 2012)
- Lower serum alpha-Klotho levels are associated with lower glomerular filtration rates and higher FGF23 levels (Pavik et al. 2013)
- Alpha-Klotho was found to be significantly and transiently affected by cinacalcet treatment (Komaba et al. 2012)
- A link between senior citizen activities of daily living (ADLs) and alpha-Klotho (Semba et al. 2011a)
- A heightened mortality risk may exist for individuals having lower circulating alpha-Klotho levels (Crasto et al. 2012)
Metabolism and calcium homeostasis
- Fetal alpha-Klotho levels are significantly increased during certain gestational stages (Godang et al. 2013)
- A possible link is found between alpha-Klotho and acromegaly (Sze et al. 2012)
- Plasma alpha-Klotho levels are affected by abnormal nutritional states (Amitani et al. 2013)
- Cardiovascular disease risk may be correlated with alpha-Klotho levels (Semba et al. 2011b)
- Low serum Klotho levels may correlate with poor vascular health (Kitagawa et al. 2013)
Immunology and inflammation
- Alpha-Klotho may have an inflammatory function (Lam-Rachlin et al. 2013)
Amitani, M. et al. Plasma klotho levels decrease in both anorexia nervosa and obesity. Nutrition 29, 1106–1109 (2013).
Crasto, C. L. et al. Relationship of low-circulating 'anti-aging' klotho hormone with disability in activities of daily living among older community-dwelling adults. Rejuvenation Res. 15, 295–301 (2012).
Godang, K. et al. Umbilical cord levels of sclerostin, placental weight, and birth weight are predictors of total bone mineral content in neonates. Eur. J. Endocrinol. 168, 371–378 (2013).
Heijboer, A. C., Blankenstein, M. A., Hoenderop, J., De Borst, M. H. & Vervloet, M. G. Laboratory aspects of circulating α-Klotho. Nephrol. Dial. Transplant. 28, 2283–2287 (2013).
Kitagawa, M. et al. A Decreased Level of Serum Soluble Klotho Is an Independent Biomarker Associated with Arterial Stiffness in Patients with Chronic Kidney Disease. PLoS One 8, (2013).
Komaba, H. et al. Effects of cinacalcet treatment on serum soluble Klotho levels in haemodialysis patients with secondary hyperparathyroidism. Nephrol Dial Transpl. 27, 1967–1969 (2012).
Kuro-o, M. et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390, 45–51 (1997).
Lam-Rachlin, J. et al. Infection and smoking are associated with decreased plasma concentration of the anti-Aging protein, -klotho. J. Perinat. Med. 41, 581–594 (2013).
Manya, H., Akasaka-Manya, K. & Endo, T. Klotho protein deficiency and aging. Geriatr. Gerontol. Int. 10, (2010).
Pavik, I. et al. Soluble klotho and autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 7, 248–257 (2012).
Pavik, I. et al. Secreted Klotho and FGF23 in chronic kidney disease Stage 1 to 5: A sequence suggested from a cross-sectional study. Nephrol. Dial. Transplant. 28, 352–359 (2013).
Semba, R. D. et al. Plasma klotho and mortality risk in older community-dwelling adults. Journals Gerontol. - Ser. A Biol. Sci. Med. Sci. 66 A, 794–800 (2011a).
Semba, R. D. et al. Plasma klotho and cardiovascular disease in adults. J. Am. Geriatr. Soc. 59, 1596–1601 (2011b).
Sze, L. et al. Excessively high soluble Klotho in patients with acromegaly. J. Intern. Med. 272, 93–97 (2012).
Utsugi, T. et al. Decreased insulin production and increased insulin sensitivity in the klotho mutant mouse, a novel animal model for human aging. Metabolism. 49, 1118–1123 (2000).
Yamazaki, Y. et al. Establishment of sandwich ELISA for soluble alpha-Klotho measurement: Age-dependent change of soluble alpha-Klotho levels in healthy subjects. Biochem. Biophys. Res. Commun. 398, 513–518 (2010).
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