Interleukin-6 contributes to the increase in fibroblast growth factor 23 expression in acute and chronic kidney disease

Significance

Fibroblast growth factor 23 (FGF23) is an endocrine member of the FGF family, expressed by osteocyte and osteoblast cells in bone. FGF23 levels are markedly increased in chronic kidney disease, correlating with increased mortality. The primary physiological action of FGF23 involves the regulation of bone and mineral metabolism through a bone-kidney-parathyroid axis. FGF23 is a phosphaturic hormone that acts on the kidney to increase phosphate excretion and suppress biosynthesis of 1,25(OH)2D3. FGF23 also acts on the parathyroid to decrease parathyroid hormone (PTH) gene expression and parathyroid cell proliferation, but in chronic kidney disease the parathyroid resists the action of FGF23 owing to a down-regulation of the FGF-receptor complex, klotho-FGF23-receptor 1. PTH in turn increases FGF23 expression in chronic kidney disease, as do other factors including phosphate retention, acidosis, vitamin D calcium and FGF receptor activation by low-molecular-weight FGFs. Inflammation and iron deficiency also stimulate FGF23 production.

Acute kidney injury is associated with high mortality and accelerated progression of chronic kidney disease. It initiates the process of necrosis and apoptosis in renal tubular epithelial cells. Acute kidney injury caused by ischemic acute renal failure and bilateral nephrectomy is associated with an increase in multiple serum cytokines including interleukin-6 (IL-6), interleukin-1β and members of the tumor necrosis factor superfamily cytokines. In addition, in patients with chronic kidney disease, an increase in FGF23 levels is associated independently with higher levels of inflammatory markers including IL-6, C-reactive protein and tumor necrosis factor-α and predicts poor clinical outcome. Higher levels of IL-6, C-reactive protein and FGF23 were all associated independently with an increased risk of death. Though much work has been done on chronic kidney disease and acute kidney injury, the roles of cytokines, particularly IL-6, in the high FGF23 levels in uremia has not been investigated.

In a recent research paper published in Kidney International, Hadassah Hebrew University Medical Center scientists in Israel Dr. Karina Durlacher-Betzer, Alia Hassan, Dr. Ronen Levi, Dr. Jonathan Axelrod, Professor Justin Silver and Professor Tally Naveh-Many embarked on a study to show that IL-6 is an important regulator of FGF23 in both acute and chronic kidney failure, that increases FGF23 expression in vitro and in vivo.

When the authors injected folic acid in mice to induce acute kidney injury they observed the expected increase in calvaria FGF23 mRNA and serum levels. Administering dexamethasone (antiinflammatory agent) prevented the increase in serum FGF23 in acute kidney injury. IL-6 knockout mice failed to increase FGF23 expression in adenine-high- phosphorus-induced chronic uremia. On the other hand, when mice were made to over-express IL-6, a large increase in FGF23 was observed. The authors studied the signaling pathways and mechanism involved and showed that this increase in FGF23 by IL-6 is via STAT3 signaling.

The study provides compelling evidence that high levels of IL-6 resulting from experimental acute and chronic kidney failure contribute to the high levels of calvaria mRNA and serum FGF23 levels. It shows that IL-6 expression is necessary for the increase in FGF23 expression in uremia which itself may itself induce inflammation. Recent studies by Singh et al suggested that FGF23 contributes to uremic inflammation by increasing hepatic expression and secretion of inflammatory cytokines, including IL-6. The findings that IL-6 increases FGF23 expression and contributes to the high levels of FGF23 in uremia complete a positive feedback loop in which IL-6 increases FGF23 expression that in turn may promote inflammation. This positive feedback loop would form a vicious cycle contributing to increased FGF23 levels. The current study highlights new approaches and potential drug targets for treatment of the high levels of FGF23 in acute and chronic kidney failure.

 

Interleukin-6-increase-in-fibroblast-growth-factor-23--Medicine-Innovates
Figure legend: A FGF23 – IL-6 feedback loop. FGF23 expression is regulated by different factors incoluding 1,25(OH)2D3 (1,25D), PTH, phosphate, iron, acidosis, estrogens, c-klotho, calcium and more. 1,25, PTH and phosphate for a feedback loop with FGF23. The study by Durlacher-Betzer et al shows that IL-6 increases FGF23 expression through STAT3 and contributes to the high levels of serum FGF23 in both acute and chronic kidney disease. FGF23 in turn increases hepatic IL-6 production. This bone-liver positive feedback loop would form a vicious cycle contributing to uremic inflammation and increased FGF23 levels.

 

References

Durlacher-Betzer, K., Hassan, |A., Levi, R., Axelrod, J., Silver, J., and Naveh-Many, T. Interleukin-6 contributes to the increase in fibroblast growth factor 23 expression in acute and chronic kidney disease, Kidney International (2018) 94, 315-325;https://doi.org/10.1016/j.kint.2018.02.026

Singh, S., Grabner, A., Yanucil, C., Schramm, K., Czaya, B., Krick, S., Czaja, MJ., Bartz, R., Abraham, R., Di Marco, GS., Brand, M., Wolf, M. and Faul, C. Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease. Kidney Int. (2016) 90, 985–996.

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