This concept was examined in the animal model of unilateral ureter obstruction (UUO) and the results showed very early vascular effects of unilateral kidney fibrosis supporting existence of a new kidney-vasculature axis . The UUO in rats caused an upregulation of activin-A in obstructed kidneys as well as a doubling of activin-A in plasma after ten days, suggesting a secretion of activin-A from the obstructed kidney with potentially systemic effects on CKD-MBD. As such, increased aortic sclerostin was observed in UUO rats, that have normal kidney function, due to the untouched contralateral kidney. In mice with CKD, a ligand trap for the activin type IIA receptor is protective against vascular disease and renal fibrosis . Compounds such as those interfering with activin type IIA receptor signalling are therefore of particular therapeutic interest as potential treatments to break this bone-vascular cross-talk in CKD .
The bone-kidney endocrine axis
A defect in the expression of Klotho gene in the mouse results in a syndrome resembling human ageing, that include a short lifespan, infertility, arteriosclerosis, skin atrophy, osteoporosis and emphysema. Since it was discovered in 1997 the Klotho gene product was suggested as a functional part of a signalling pathway that regulates ageing in vivo and morbidity in age-related diseases, including uraemia . However, its functions remained somewhat unclear until the discovery of FGF-23, which is mainly produced in the bone. The experimental studies suggested FGF-23 as an important in vivo regulator of phosphate homeostasis and vitamin D metabolism in the kidney. Strikingly similar physical and biochemical phenotypes of mice that lack either Fgf-23 or Klotho gene were then demonstrated , and a functional relationship between these molecules postulated. This has led to the identification of Klotho as a cofactor in FGF-23 and FGF receptor interactions . FGF-23-Klotho complex counter regulates plasma vitamin D levels, by modulating the renal 1α-hydroxylase, and phosphate levels, by suppressing sodium–phosphate co-transporter activities.
Klotho is a membrane-bound protein primarily expressed in the kidney, mostly in the distal tubule and, at a low level, in the proximal tubule. The kidney is essential in Klotho homeostasis, both producing Klotho and releasing it into the circulation, as well as clearing it from blood into the urine [10-12]. Obstructed kidneys showed early Klotho gene depletion and induction of pro-fibrotic TGF- and periostin. Contralateral kidneys exhibited no compensatory upregulation of Klotho, suggesting importance of kidney mass for Klotho production .
Both FGF-23 and Klotho deficiencies result in phosphate retention and premature ageing syndrome. The animal studies on FGF-23 and Klotho-deficient mice have been pivotal in linking phosphate levels and longevity in mammals . The transgenic overexpression of Klotho in mice extended their life span through inhibition of insulin and IGF1 signalling . In addition, soluble Klotho restored phosphate retention, suppressed accelerated ageing and significantly reduced both renal and aorta calcium deposits in Klotho mutant mice . These results created a hope for a therapeutic potential of soluble Klotho protein in treatment of age-related disorders bearing in mind the relationship between Klotho deficiency and accelerated ageing in uraemia.
Despite the evidence that Klotho is neither expressed in normal nor uraemic aorta , there are several vascular effects such as protection of vascular smooth muscle cells against calcification, resistance to oxidative stress, maintenance of endothelial function and integrity, that are presumably mediated via its soluble form . However, strategies to upregulate endogenous Klotho might prove challenging – a blockade of FGF receptor upregulated normal kidney Klotho gene and protein expression but had no effect on the kidney in long term uraemic rats .
The recent crystal structure of FGF-23-soluble Klotho-FGF receptor complex revealed that soluble and transmembrane Klotho possess a similar capacity for FGF-23 signalling and it was therefore suggested that all pleiotropic effects of Klotho are FGF-23 dependent . However, it seems that in the absence of FGF-23, the receptor-binding arm of Klotho may interact with specific carbohydrates and exert its pleiotropic FGF-23 independent activities. Local and distant anti-fibrotic and anti-tumorigenic effects are mediated at least partially by the direct inhibitory effects of soluble Klotho on TGFβ1 signaling, Wnt signaling, and FGF signalling (Figure 2) .