The aging suppressor klotho: a potential regulator of growth hormone secretion

Abstract

Klotho is a transmembranal protein highly expressed in the kidneys, choroid plexus, and anterior pituitary. Klotho can also be cleaved and shed and acts as a circulating hormone. Klotho-deficient mice (kl/kl mice) develop a phenotype resembling early aging. Several lines of evidence suggest a role for klotho in the regulation of growth hormone (GH) secretion. The kl/kl mice are smaller compared with their wild-type counterparts, and their somatotropes show reduced numbers of secretory granules. Moreover, klotho is a potent inhibitor of the IGF-I pathway, a negative regulator of GH secretion. Therefore, we hypothesized that klotho may enhance GH secretion. The effect of klotho on GH secretion was examined in GH3 rat somatotrophs, cultured rat pituitaries, and cultured human GH-secreting adenomas. In all three models, klotho treatment increased GH secretion. Prolonged treatment of mice with intraperitoneal klotho injections increased mRNA levels of IGF-I and IGF-I-binding protein-3 mRNA in the liver, reflecting increased serum GH levels. In accord with its ability to inhibit the IGF-I pathway, klotho partially restored the inhibitory effect of IGF-I on GH secretion. Klotho is known to be a positive regulator of basic bFGF signaling. We studied rat pituitaries and human adenoma cultures and noted that bFGF increased GH secretion and stimulated ERK1/2 phosphorylation. Both effects were augmented following treatment with klotho. Taken together, our data indicate for the first time that klotho is a positive regulator of GH secretion and suggest the IGF-I and bFGF pathways as potential mediators of this effect.

Klotho and fibroblast growth factor 23 in cerebrospinal fluid in children

“…A similar correlation was previously noted between plasma sKlotho and body length in neonates [56]. In this context, Shahmoon et al recently demonstrated that Klotho is a positive regulator of growth hormone secretion with IGF-I and basic FGF as potential mediators of this effect [57]. But nevertheless, specific abnormalities of growth hormone secretion or pituitary function in FGF23 null mice have not been documented despite severe growth retardation of these mice, indicating that GH regulation by Klotho might be FGF23-independent.…”

Tissue expression and source of circulating αKlotho

“…The anterior pituitary was early pinpointed as a Klotho-expressing tissue [1], which was corroborated by later studies [52,57,65,95]. Notably, Growth Hormone (GH)-producing adenomas express lower levels of Klotho mRNA than normal pituitary tissue, whereas nonfunctional adenomas have higher Klotho expression [96]. Neidert et al showed that Klotho protein was expressed diffusely in adenoma and in lobular fashion in normal pituitary, only partially overlapping with GH-positive cells [97].…”

Molecular and cellular aspects of age-related cognitive decline and Alzheimer’s disease

“…In humans, polymorphisms of KL have been associated with life span and several age-associated diseases, including atherosclerosis, hypertension, osteoporosis, chronic kidney failure, and cancer [239–243]. A possible connection between Klotho and IGF-1R has also been delineated [237,244,245]. Human variations that lead to increased circulating levels of Klotho are associated with greater cortical volumes in the brain [246].…”