Phosphate-Lowering Therapy Attenuates Atherosclerosis by Restoring SCAP-SREBP2 Pathway in Patients with CKD

Background: Hyperphosphatemia, a common complication of chronic kidney disease (CKD),has been identified as the primary atherogenic factor due to its disruption of sterol regulatory element banding protein (SREBP) cleavage activating protein (SCAP)-controlled intracellular cholesterol homeostasis. The present study aimed to investigate whether phosphate-lowering therapy attenuates hyperphosphatemia-aggravated atherosclerosis by correcting the SCAP/SREBP2 pathway. Methods: A retrospective case-control study was performed in CKD patients receiving maintenance hemodialysis (MHD) and combined with hyperphosphatemia. The hyperphosphatemic animal model was established by high phosphate diet (HPD) feeding, and phosphate lowering drug sevelamer was prescribed to normalize the serum level of phosphate. Results: The retrospective case-control study suggested the benefits for diminution of Atherosclerotic cardiovascular disease (ASCVD) risk by phosphorus-lowering drugs in 704 CKD patients receiving MHD and combined with hyperphosphatemia. Meanwhile, the use of sevelamer in the treatment of hyperemia was found to significantly reduce atherosclerotic plaque burden through animal studies. It was likely resulted from the restoration of the SCAP-SREBP2-HMGCR signaling for the negative feedback control of intracellular cholesterol hemostasis Conclusion: Phosphate-lowing therapy could disrupt atherogenesis exacerbated by hyperphosphatemia via recovering SCAP mediated feedback regulation of intracellular cholesterol de novo biosynthesis. Prevention or early control of hyperphosphatemia would benefit CKD patients from ASCVD, those phosphate-lowing pharmaceuticals might be a supplementary therapy of statins to alleviate atherogenesis in CKD population Funding: Other NIH Support - the Young Scientists Fund of the National Natural Science Foundation of China (No. 82100774 and No. 81500341),CQMU Program for Youth Innovation in Future Medicine (No. W0162 )Sevelamer overrode the increment of HMGCR expression induced by HPD in ApoE-/- mice