Monday, December 22, 2008

Klotho information

I went to an afternoon of lectures at ASN on Klotho and its relationship to calcium. I thought they talked about klotho being involved with proximal tubule transcellular calcium reabsorption via TRPV5/6 but after posting a comment about that here, I find that my memory failed me.

It looks like Klotho binds FGF-23 receptor and makes it more specific for binding FGF-23 which then increases the production of calcitriol. Additionally free Klotho in the urine increases expression of TRPV5/6 which enhances DCT and connecting tubule transcellular calcium absorption.

the Recent advances that have given rise to marked progress in clarifying actions of alpha-Klothootho (alpha-Klotho) and FGf23 can be summarized as follows:
  1. alpha-Klotho binds to Na, K-ATPase, and Na, K-ATPase is recruited to the plasma membrane by a novel alpha-Klotho dependent pathway in correlation with cleavage and secretion of alpha-Klotho in response to extracellular Ca.
  2. The increased Na gradient created by Na, K-ATPase activity drives the transepithelial transport of Ca in the choroid plexus and the kidney, this is defective in alpha-Klotho(-/-) mice.
  3. The regulated PTH secretion in the parathyroid glands is triggered via recruitment of Na, K-ATPase to the cell surface in response to extracellular Ca concentrations.
  4. alpha-Klotho, in combination with FGF23, regulates the production of 1,25 (OH) Vitamin D in the kidney. In this pathway, alpha-Klotho binds to FGF23, and alpha-Klotho converts the canonical FGF receptor 1c to a specific receptor for FGF23, enabling the high affinity binding of FGF23 to the cell surface of the distal convoluted tubule where alpha-Klotho is expressed.
  5. FGF23 signal down-regulates serum phosphate levels, due to decreased NaPi-IIa abundance in the apical membrane of the kidney proximal tubule cells.
  6. alpha-Klotho in urine increases TRPV5 channel abundance at the luminal cell surface by hydrolyzing the N-linked extracellular sugar residues of TRPV5, resulting in increased Ca influx from the lumen. 
These findings revealed a comprehensive regulatory scheme of mineral homeostasis that is illustrated by the mutually regulated positive/negative feedback actions of alpha-Klotho, FGF23, PTH and 1,25 (OH) Vitamin D. In this regard, alpha-Klotho and FGF23 might play pivotal roles in mineral metabolism as regulators that integrate calcium and phosphate homeostasis, although this concept requires further verification in the light of related findings. Here, the unveiling of the molecular functions of alpha-Klothootho and FGF23 has recently given new insight into the field of calcium and phosphate homeostasis. Unveiled molecular functions of alpha-Klotho and FGF23 provided answers for several important questions regarding the mechanisms of calcium and phosphate homeostasis that remained to be solved, such as :
  1. What is the non-hormonal regulatory system that directly responds to the fluctuation of extracellular Ca? 
  2. How is Na, K-ATPase activity enhanced in response to low calcium stimuli in the parathyroid glands?
  3. What is the exact role of FGF23 in calcium and phosphorus metabolism?
  4. How is Ca influx through TRPV5 controlled in the DCT nephron?
  5. How is calcium homeostasis regulated in cerebrospinal fluid?
However, several critical questions still remain to be solved. So far reported,alpha-Klotho binds to Na, K-ATPase, FGF receptors and FGF23, and alpha-Klotho hydrolyzes the sugar moieties of TRPV5. Does alpha-Klotho recognize these proteins directly or indirectly?Is there any common mechanism?How can we reconcile such diverse functions of alpha-Klotho?What is the Ca sensor machinery and how can we isolate it?How do hypervitaminosis D and the subsequently altered mineral-ion balance lead to the multiple phenotypes?What is the phosphate sensor machinery and how can we isolate it? How does the Fgf23/alpha-Klotho system regulate phosphorus homeostasis? How are serum concentrations of Ca and phosphate mutually regulated?

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