Fgf23klotho axis in ckd renal replacement therapy full text. The findings of this study point to an important role of klotho in. The addition of skl reversed the effect of klotho kd, and brought translocation close to the sham control. In mice, the overexpression of the kl gene extends the lifespan, whereas mutations to the kl gene shorten the lifespan. Googling the function of klotho seems to indicate that its a downregulator for vitamin d production, and the reduction in lifespan in klothodeficient mice goes away if you restrict vitamin d. Contributes to the transcriptional repression of cholesterol 7alphahydroxylase cyp7a1, the ratelimiting enzyme in bile acid synthesis. Jan 17, 2018 crystal structures of free and ligandbound.
The klotho gene and soluble klotho in health and disease. Fgf23 works by binding to klotho fgf receptor fgfr complex. So the fact that people upregulate klotho in response to high levels of vitamin d derivatives is not surprising. May have weak glycosidase activity towards glucuronylated steroids. Googling the function of klotho seems to indicate that its a downregulator for vitamin d production, and the reduction in lifespan in klothodeficient mice goes away if you restrict. The aim of the present study was, therefore, to characterize renal klotho protein expression and to elucidate the mechanisms through which klotho is shed by determining the effects of adammmp inhibition on klotho shedding in vitro and in vivo. Elisa kits detecting klotho can be used to research aging and bone loss or to study chronic renal failure crf. Klotho is mainly expressed in kidney distal tubule. Klotho only increases post exercise in people who completed a 16week training program, with younger people having a.
Despite the lack of klotho in the kidney where endogenous klotho expression is most abundant, the efmkl48 allele was able to rescue the aginglike phenotypes when introduced into the klotho deficient mice, indicating that expression in the kidney may not be essential for klotho protein function. In 1997, an accidental insertion of a transgene led to creation of transgenic mice with several agerelated disorders. Applications of klotho protein delay dementia, kidney. We thus hypothesized that the metabolic fgf21klbfgfr1 pathway is involved in chh. Nearly 10 years later, we demonstrated that klotho functions as the obligate co receptor for fibroblast growth factor 23 fgf23, a finding that. However, it lacks essential active site glu residues at positions 241 and 874, suggesting it may be inactive as a. The klothotreated mice also learned better and were more willing than untreated mice to explore new territory, even. This protein plays a major role in regulating the phosphate levels within the body phosphate homeostasis. Variants of this antigen may also be found in other species, including canine, porcine, monkey, mouse and rat. Apr 16, 2019 the three endocrine fibroblast growth factors fgfsfgf19, fgf21, and fgf23are circulating hormones that regulate critical metabolic processes in liver, adipocytes, hypothalamus, and kidney. Klotho is a membranebound or soluble antiaging protein, whose protective activity is essential for a proper function of many organs. The protein may also be known as bkl, betaklotho, and bklotho. Three major functions have been proposed, i a hormonal function of soluble klotho, ii an enzymatic function as.
It plays a major role in regulating kidney function and vascular health. We investigated whether klotho levels and signaling modulate inflammation in diabetic kidneys. Jul 24, 2014 alzheimers disease is the most frequent agerelated dementia affecting 5. Taylor2, moosa mohammadi3, ann canfield2, karolina kublickiene4, tobias e.
Thus, soluble klotho compensated for the depletion of cellular klotho. Klotho and the aging process the korean journal of internal. Klotho protein antiaging benefits and improved cognition. Skeletal muscle as a regulator of the longevity protein, klotho. New insights into the mechanism of action of soluble klotho.
The name of the gene, klotho, is that of the fate in. The kl gene provides instructions for making the protein alphaklotho, which is found primarily in kidney cells. The function and pathophysiological implications of klotho in ckd coreceptor of fgf23. Most patients with klb mutations 9 exhibited metabolic defects. This formulation results in lower efficiency of binding of the protein by itself and. While an association between muscle function and klotho expression has been previously suggested from longitudinal cohort studies, a direct relationship between circulating. Read on to learn about genetic and environmental factors that may increase it.
Three major functions have been proposed, a hormonal function of soluble klotho, an enzymatic function as glycosidase, and the function as an obligatory coreceptor for fgf23 signaling. Current published literature regarding the klotho gene and soluble klotho together and apart include an estimated 3,599. In 2 cohorts of seniors, klotho was a significant predictor of improved executive. The role of klotho in chronic kidney disease bmc nephrology. Alcohol is a widely consumed drug in western societies that can lead to addiction.
Klb has two extracellular glycosidase domains that lack a characteristic glutamic acid residue essential for enzymatic activity. This chapter overviews function of klotho family proteins as obligate coreceptors for endocrine. Research design and methods renal klotho expression was determined by quantitative realtime pcr and immunoblot analysis. Objective klotho is an antiaging hormone present in the kidney that extends the lifespan, regulates kidney function, and modulates cellular responses to oxidative stress. The antiaging protein klotho is induced by gaba therapy and. Because klotho lacks the glutamic acid residues that have been shown to be involved in the catalytic activity of this family of enzymes, the function of this protein was unknown. The gamma and the beta function delft university of. Klotho serves as a primary zip codelike receptor that acts as a targeting. Insights into structurefunction and ptms of soluble klotho. This protein plays a major role in regulating the phosphate levels within the body. Klotho protein for longevity delay dementia, kidney disease. A small shift in consumption can have dramatic consequences on public health. Mice engineered to lack this gene seem to like alcohol much more and certainly choose to drink more alcohol than. The klotho treated mice also learned better and were more willing than untreated mice to explore new territory, even though their brains.
Klotho has several glycosylation sites, it looks like putative 116 kda and the glycosylated form around 5 kda are both correct. Recombinant human klotho protein active ab84072 abcam. Pdf klotho is an antiaging protein that is mostly secreted by the kidneys, the brain, and the thyroid. The protein may also be known as bkl, beta klotho, and b klotho. Update on fgf23 and klotho signaling sciencedirect. Secreted klotho protein also protects cells and tissues from oxidative stress through a mechanism yet to be identified. Increases the ability of fgfr1 and fgfr4 to bind fgf21 by similarity. Klotho is a substrate for alpha, betaand gammasecretase. Structurefunction relationships of the soluble form of the antiaging. Aging of skeletal muscle is concomitant with a decrease in muscle stem cell function resulting in impaired regeneration. Klotho protein exists in several forms including the fulllength membrane form mkl and a soluble circulating form soluble klotho skl. Loss of cognition, kidney failure, diabetes, and cancer are all things that are believed to be associated with the bodys production of this klotho protein. Nov 28, 2016 the gene is called beta klotho, and it seems to act as a brake on drinking alcohol. Genetic screening of 334 chh patients identified seven heterozygous lossof function klb mutations in patients 4%.
The reported amino acid length is 1044 and the expected mass is 119. The gamma and the beta function as mentioned in the book 1, see page 6, the integral representation 1. Klotho gene delivery through a viral carrier has been shown to effectively improve multiple pathophysiological phenotypes in klothodeficient mice, thereby preventing the progression of kidney damage in rat models and improving vc and endothelial function in ckd. Klotho therapeutics kti is using biotechnology to mimic the human protein. Canonical fgfs require heparan sulfate proteoglycans to activate fgf receptors, but endocrine fgfs instead depend on klotho proteins for this process. Klotho is a protein that plays a role in intelligence and longevity. The functional role of the klotho protein is still a controversial issue. Klotho plays a major role in kidney disease as much of the klotho protein circulating in the blood is produced in the kidneys. Klotho, a natural human protein has great potential to delay these diseases of aging.
A systematic dissection of sequence elements determining. Increase longevity and intelligence with boosted klotho levels. Klotho levels are known to decline in chronic kidney disease ckd and may be an early marker of this disease 1. Klotho protein is expressed predominantly in the kidneys. Antiaging protein alpha klothos molecular structure. Klotho is an antiaging protein that is mostly secrete by the kidneys, the brain, and the thyroid. Klotho kd resulted in spontaneous translocation of p65 fig. Biotechne appreciates the critical role that you and our products and services play in research efforts to further scientific innovation and discovery. Klotho deficiency may be one of the causes for ckd progression and resulting complications including. How to increase klotho protein levels in the body health. The endocrine fibroblast growth factors fgf19, fgf21 and fgf23 are circulating hormones that regulate important metabolic and physiological functions in vertebrates. Like klotho, klotho beta facilitates binding between fgf19 subfamily members and their receptors via formation of a ternary complex 3. Klotho is an antiaging gene, and mutation of the mouse klotho gene leads to premature aging syndrome 35. Klotho, also known as alphakl, is a full name of klotho.
Nov 17, 2017 the klotho gene encodes a type i singlepass transmembrane protein that contains a large extracellular domain, a membrane spanning segment, and a short intracellular domain. In addition, fgf23 suppresses intestinal phosphate absorption by reducing 1,25. Klotho protein is a naturally occurring substance in the body that has been described as an antiaging protein by scientists. The aim of the present study was, therefore, to characterize renal klotho pro. Klotho is a wellknown antiaging hormone, which serves as a suppressor of aging through a variety of mechanisms. Klotho was originally discovered as an antiaging factor, but the functional role of klotho is still a controversial issue.
Recombinant aklotho may be prophylactic and therapeutic for acute to chronic kidney disease progression and uremic cardiomyopathy ming chang hu1,2, mingjun shi2, nancy gillings2. Peripheral elevation of a klotho fragment enhances brain. Endocrine fgfs mediate their cellular responses by binding to and stimulating complexes composed of an fgf receptor bound to either an. The biological role of klotho protein in the development of. Many studies have shown that fgf23 not only increases the urinary excretion of phosphate but also indirectly suppresses intestinal phosphate absorption by downregulating the production of 1. Here we describe the crystal structures of free and ligandbound. This paper describes the threedimensional structure of fgf19ct bound to sklb and provides mechanistic insights into the mode of action of endocrine fgfs. Aging of skeletal muscle is concomitant with a decrease in. There are several pros to having increased klotho levels, but one of the biggest is the fact that an overexpression, or excess amount of klotho production, has been shown to lead to a longer. It declines with age, in conjunction with cognitive deficits 1, 2, 3. Klotho is a powerful longevity protein that has been linked to the prevention of muscle atrophy, osteopenia, and cardiovascular disease. Variation in the klotho gene is associated with bigger brain volume and better function in human studies.
The recombinant human klothobeta protein is formulated in pbs, 50%vv glycerol and 0. The biological role of klotho protein in the development. Klotho levels are known to decline in chronic kidney disease ckd. Longevity hormone boosts memory and protects against brain. Here we investigate the functional role of the antiaging hormone klotho for muscle stem cell function after cardiotoxininduced injury of skeletal muscle using.
Klotho are generated from the same gene, they share distinct functions. Similar antiaging effects have also been ascribed to exercise and physical activity. Diseases associated with kl include tumoral calcinosis, hyperphosphatemic, familial, 3 and tumoral calcinosis, hyperphosphatemic, familial. Metadichol a novel agonist of the antiaging klotho gene. Jun 17, 2014 klotho is a powerful longevity protein that has been linked to the prevention of muscle atrophy, osteopenia, and cardiovascular disease. Structure and expression of klotho the klotho gene is composed of five exons 6, 7 and encodes a type 1 singlepass transmembrane glycoprotein 1014 and 1012 amino acids in mouse and human. May 23, 2016 fibroblast growth factor 23 fgf23 is a bonederived hormone regulating phosphate and vitamin d metabolism. It declines with age, in conjunction with cognitive deficits 1, 2, 3, 4. In klotho deficient mice, the inherited phenotypes closely resemble human aging, while in an animal model of klotho overexpression, the. The klotho gene encodes a singlepass transmembrane protein that forms a complex with multiple fibroblast growth factor fgf receptors and functions as an obligatory coreceptor for. Mcewen and morrison, 20 may represent new treatment strategies.
Moreover, the tissuespecific unique biologic activity of fgf23 is likely to be regulated by a limited local distribution of klotho. Fgf23 reduces serum phosphate level by suppressing the expression of type 2a and 2c sodiumphosphate cotransporters in the renal proximal tubules. Klotho is a protein that circulates in the blood and brain throughout life. Arterial klotho expression and fgf23 effects on vascular. Thus, the transmembrane and secreted forms of klotho protein have distinct functions, which may collectively affect aging processes in mammals. Klotho, are essential components of endocrine fibroblast growth factor fgf receptor complexes, as they are required for the highaffinity. Klotho beta klb encodes a kda type 1 transmembrane protein with a short 29 amino acids intracellular domain that has no predicted kinase activity. Arterial klotho expression and fgf23 effects on vascular calcification and function karolina lindberg1, hannes olauson1, risul amin1, arvind ponnusamy2, regina goetz3, rebecca f. By contrast, the function and mechanism of action of skl are less clear. Moreover, the prevention of klotho decline by several mechanisms can attenuate renal injuries, retard ckd progression, ameliorate extrarenal complications, and improve renal function. Liverspecific activities of fgf19 require klotho beta. The three endocrine fibroblast growth factors fgfsfgf19, fgf21, and fgf23are circulating hormones that regulate critical metabolic processes in liver, adipocytes. Giving klotho to these mice improved their motor function.
Klotho beta is expressed primarily in the liver and pancreas and functions as a cofactor for fgf19 subfamily member interactions with their receptors. Recombinant human klotho beta protein, cf 5889kb050. The discovery of the klotho kl gene, which was originally identified as a putative agingsuppressor gene, has generated tremendous interest and advanced understanding of the aging process. The kl gene provides instructions for making the protein alpha klotho, which is found primarily in kidney cells. Klotho beta, a divergent structural member of the glycosidase i superfamily, is expressed primarily in the liver and pancreas, with lower expression in adipose tissue 1, 2.