Adiponectin alters renal calcium and phosphate excretion through regulation of klotho expression

Abstract

The kidney controls systemic calcium and phosphate levels and disturbances of its control mechanisms can lead to a variety of diseases. The insulin-sensitizing adipokine adiponectin is renoprotective and accelerates functional recovery following renal injury. However, unlike other adipokines, adiponectin is reduced in obesity. High adiponectin levels are also correlated with bone loss, suggestive of an additional action in mineral metabolism. Using knockout, wildtype, and adiponectin overexpressing transgenic mice, we sought to identify the mechanistic basis for adiponectin’s ability to regulate calcium and phosphate balance at the level of the kidney. Adiponectin knockout mice exhibited lower serum calcium, lower urinary calcium excretion and markedly lower serum fibroblast growth factor 23 (FGF23) levels, although circulating klotho concentrations were significantly higher than in wildtype littermates. The transgenic mice exhibited lower bone mass and strength, particularly compared to adiponectin knockout mice. The transgenic mice were hyper-responsive to 2% phosphate-enriched diet, exhibiting 2-fold higher serum FGF23 and concomitantly higher fractional phosphate excretion. These mice also excreted more calcium with calcium-enriched diet and had less renal klotho protein expression. In contrast, the knockout mice exhibited a smaller increase in FGF23 and maintained elevated klotho levels on both mineral challenges. Kidney-specific adiponectin expression in doxycycline-inducible adiponectin mice and adiponectin addition in vitro confirmed adiponectin’s ability to reduce tubular epithelial cell klotho secretion. Thus, adiponectin alters calcium and phosphate balance and renal mineral excretion, in part, through klotho. This work highlights the profound effects of adipose tissue on renal function and has identified a new mechanism by which adiponectin may regulate bone mass.

Bone Metabolism Parameters in Hemodialysis Patients With Chronic Kidney Disease and in Patients After Kidney Transplantation

“…The reasons for this phenomenon are currently unknown. Tan et al showed that Klotho concentrations were not related to the reduction of immunosuppression or to biochemical blood parameters, and, therefore, suggested non-renal related causes of the increased Klotho concentrations (Tan et al 2017). In our study, we also found the Klotho concentrations to be highest in patients after kidney transplantation.…”

“…Previous studies reported that high concentrations of adiponectin were negatively correlated with bone density (Naot et al 2017). Recent animal studies confirmed the ability of adiponectin to reduce Klotho secretion by renal tubular cells and, therefore, confirmed the influence of adiponectin on the regulation of bone mass (Rutkowski et al 2017). Leptin can directly stimulate bone cells to form bone tissue (Cornish et al 2002).…”

Role of Adipokines and Interleukin-17 in the Regulatory Mechanism of Bone Remodeling in Rat Model of Kidney Function Disorder

“…In rats with kidney function disorder model all the cytokines have elevated levels (p<0.05). These data correlate with literature [4][5][6][7]. Analysis of their interrelations showed that in the intact rats it was no correlation between adiponectin and visfatin levels, weak positive correlation between adiponectin and IL-17 and weak negative correlation between visfatin and IL-17 was shown.…”

Klotho regulation by albuminuria is dependent on ATF3 and endoplasmic reticulum stress

“…Genotyping was performed as described. 45 Podocyte apoptosis was induced by injection of the dimerizer AP20187 (#635058; Takara, Saint-Germainen-Laye, France). Transgenic male FVB mice aged 8 weeks were injected intraperitoneally with a single dose of 0.5 μg/g body weight of dimerizer 44 or equal volume of vehicle and euthanized after 3 or 7 days.…”