Abstract
Plasma levels of phosphate and all-trans retinoic acid (atRA), the active body of vitamin A, increase in patients with chronic kidney disease (CKD). Although hyperphosphatemia in CKD worsens the disease state and renal dysfunction, the effect of atRA on phosphate metabolism in the body was unclear, especially with reference to the pathophysiology of CKD. We revealed that atRA regulated phosphate homeostasis in the body through the positive and negative regulation of phosphate (re)absorption in the kidney and intestine of rats. While atRA induces muscle differentiation, the effect of atRA on the skeletal muscle other than muscle differentiation was unknown. We revealed that atRA increased growth arrest and DNA damage-inducible protein 34 (GADD34) expression depending on MAPK signal in the skeletal muscle of mice, resulting in muscle fiber type change, which was the same as a change in the type of muscle atrophy in CKD. An excess of saturated fatty acid is associated with a decline in kidney function and cardiovascular diseases as a complication of CKD. We demonstrated that phosphate-induced accumulation of saturated fatty acid in vascular smooth muscle cells elicits vascular calcification via endoplasmic reticulum stress in CKD. These findings suggest a possibility that inhibition of increases in phosphate and atRA contents in the body of CKD patients can become a target for therapeutic strategies.
