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Role of alpha Klotho in Chronic Kidney Disease, Metabolism, & Aging

Posted by Brandon Savela on Jul 20th 2017

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 ELISA kit to study this protein target, which has been found to play a role in:

  • Chronic kidney disease (CKD)
  • Aging
  • Metabolism and calcium homeostasis
  • Cardiovascular disease
  • Inflammation

Expression of alpha Klotho

Alpha Klotho is preferentially expressed in parathyroid glands, the kidney distal convoluted tubules, and the brain choroid plexus (1). 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 (2).

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 /klmice blood glucose and insulin levels were significantly lower and insulin sensitivity was much higher compared to wild-type mice (3). In addition, soluble alpha Klotho helps regulate mineral metabolism, including circulating calcium and inorganic phosphate homeostasis (4). Manya et al. describe four alpha Klotho mediated pathways, including calcium channel activity, insulin/IGF signal inhibition, FGFR1(IIIc) binding and conversion to FGF23 receptor, and alpha1-Na+, K+-ATPase binding and recruitment of the Na+, K+-ATPase complex (1). Two of these Klotho pathways are illustrated below.

Measuring alpha Klotho

The Human soluble alpha-Klotho Assay (Cat.# 27998) 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 (4). This alpha Klotho ELISA can be used to accurately detect and measure human circulating 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 subjects with chronic kidney disease. In this experiment, the within- and between-run variations of the assay were <5% and <8%, respectively (5). 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 (6)
  • Lower serum alpha Klotho were associated with lower glomerular filtration rates and higher FGF23 levels (7)
  • Alpha Klotho was found to be significantly and transiently affected by cinacelcet treatment (8)

Aging

  • A link between senior citizen activities of daily living (ADLs) and alpha Klotho (9)
  • A heightened mortality risk may exist for individuals having lower circulating alpha Klotho levels (10)

Metabolism and Calcium Homeostasis

  • Fetal alpha-Klotho levels are significantly increased during certain gestational stages (11)
  • A possible link is found between alpha-Klotho and acromegaly (12)
  • Plasma alpha-Klotho levels are affected by abnormal nutritional states (13)

Cardiovascular Disease

  • Cardiovascular disease risk may be correlated with alpha-Klotho levels (14)
  • Low serum Klotho levels may correlate with poor vascular health (15)

Immunology and Inflammation

  • Alpha-Klotho may have inflammatory function (16)

References
1. Manya, H., et al. (2010) Geriatr. Gerontol. Int. 10 (Suppl. 1):S80.
2. Kuro-o, M., et al. (1997) Nature 390:45.
3. Utsugi, T., et al. (2000) Metabolism 49(9):1118-1123.
4. Yamazaki, Y., et al. (2010) Biochem. Biophys. Res. Commun. 398:513.
5. Heijboer, A.C., et al. (2013) Nephrol. Dial. Transplant. 0:1.
6. Pavik, I., et al. (2012) Clin. J. Am. Soc. Nephrol. 7:248.
7. Pavik, I., et al. (2013) Nephrol. Dial. Transplant. 28(2):352.
8. Komaba , H., et al.(2012) Nephrol. Dial. Transplant. 27(5):1967.
9. Semba, R.D., et al. (2011) J. Gerontol. A Biol. Sci. Med. Sci. 66A:794.
10. Crasto, C.L., et al. (2012) Rejuventation Res. 15(3):295.
11. Godang, K., et al. (2013) Eur. J. Endocrinol. 168:371.
12. Sze, L., et al. (2012) J. Int. Med. 272(1):93.
13. Amitani, M., et al. (2013) Nutrition 29(9):1106.
14. Semba, R.D., et al. (2011) J. Amer. Geriatrics Soc. 59(9):1596.
15. Kitagawa, M., et al. (2013). PLoS ONE 8(2): e56695.
16. Lam-Rachlin, J., et al. (2013) J. Perinatal Med. 0(0):1.

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