Growth hormone and Klotho

Abstract

Acromegaly is characterized by excessively high GH and IGF1 levels. Recent data suggest that soluble Klotho (sKlotho) is also elevated in patients with active acromegaly. sKlotho decreases towards normal following removal of the GH-producing pituitary adenoma. The Klotho gene was identified in mice following its accidental disruption by ectopic DNA. It is an ageing suppressor gene of restricted expression (mainly in kidneys, brain, and parathyroid and pituitary glands) encoding a transmembrane protein, mKlotho. mKlotho serves as a co-receptor in fibroblast growth factor 23 (FGF23) signalling. FGF23 promotes urinary phosphate excretion and inhibits the synthesis of calcitriol. The ectodomain of mKlotho is enzymatically released to result in a humoral factor, sKlotho, which exerts systemic effects (on ion channels and signalling pathways), possibly by working as an enzyme that modifies glycans of cell surface glycoproteins. GH enhances renal phosphate reabsorption and calcitriol production, i.e. exerts effects in the proximal tubule opposing those attributed to mKlotho, and attenuates calciuria in the distal tubule similar to sKlotho. sKlotho can be measured in extracellular fluids (serum, urine and cerebrospinal fluid (CSF)) by an ELISA. In line with predominant expression of Klotho in kidneys and choroid plexus, concentrations of sKlotho are particularly high in urine and CSF. Determination of sKlotho in serum and urine (both presumably reflecting GH action on the kidneys) could be used as a supplementary tool in the diagnosis and follow-up of patients with acromegaly. The question arises whether GH exerts selected actions via modifying activities of Klotho.

Rozpuszczalne białko α-Klotho — nowy marker aktywności akromegalii?

“…It is suggested that increased mKlotho-proteolytic enzymes activity could lead to decreasing mKlotho and to impaired FGF23 signalling, which explains FGF23 resistance. As a consequence of increased activity of enzymes, sKlotho is increased and contributes to IR [7]. As we observed in our previous study 25(OH)D correlated positively with IGF-1 only in AA group [19].…”

“…It was shown that Klotho-deficient mice (kl/kl) had a shortened life and a lot of disorders caused by human ageing, including atherosclerosis, osteoporosis, skin atrophy, and pulmonary emphysema [5]. On the other hand, overexpression of Klotho prolongs the lifespan [6,7]. Various functions of Klotho have been described until now.…”

“…It is known that in acromegaly there are high levels of FGF-23, phosphate, and calcitriol and also FGF-23 resistance [13][14]16]. On the other hand, it was shown that the high level of sKlotho is a consequence of increased pituitary GH secretion, and higher pituitary transmembrane Klotho expression was not observed [7,12] . The aim of our case-control study was to assess the serum levels of soluble a-Klotho in acromegalic patients in relation to the activity of disease and to compare it with the control group (CG).…”

Diabetic Nephropathy from RAAS to Autophagy: The Era for New Players

“…Soluble αKlotho is released through cleavage of the extracellular domain from membrane αKlotho by secretases to function as an endocrine/paracrine substance [26][27][28][29]…”

New Insights into the Interaction between Increased Iron-Deposition in the Kidney and Vitamin D/Klotho Axis in Diabetic Nephropathy

“…The soluble α klotho is characterized by his anti-apoptotic effects especially in DN. Several studies have shown that α klotho expression is decraesed in the renal PCT cells in early stages of DN, in humans and mice model [30,31] Interesting cross talk exist between α klotho-Vitamin D/ Vitamin D receptor-(VDR) axis. Up regulation or restoration of klotho by 1,25(OH)2D3, may provide a mean to slow down the progression of chronic diabetic kidney disease (CDKD).…”