期刊
KIDNEY INTERNATIONAL
卷 98, 期 6, 页码 1449-1460出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.kint.2020.06.045
关键词
cortical collecting duct; hypercholesterolemia; nephrotic syndrome; PCSK9
资金
- National Institutes of Health [K01DK096127]
- AHA Scientist Development Grant [16SDG27500017]
The proprotein PCSK9 functions as a chaperone for the epithelial sodium channel in the cortical collecting duct (CCD), is highly expressed in the liver, and plays a significant role in the pathogenesis of hypercholesterolemia. Lower levels of PCSK9 expression also occur in the normal kidney and intestine. Here, we found increased PCSK9 expression in the CCD of biopsies of patients with primary glomerular disease and explored a possible relationship with hypercholesterolemia of nephrotic syndrome. Significantly elevated serum PCSK9 and cholesterol levels were noted in two models of focal and segmental glomerulosclerosis, the Rrm2b-/- mouse and the Buffalo/Mna rat. Increased expression of PCSK9 in the kidney occurred when liver expression was reduced in both models. The impact of reduced or increased PCSK9 in the CCD on hypercholesterolemia in nephrotic syndrome was next studied. Mice with selective deficiency of PCSK9 expression in the collecting duct failed to develop hypercholesterolemia after injection of nephrotoxic serum. Blocking epithelial sodium channel activity with Amiloride in Rrm2b-/- mice resulted in increased expression of its chaperone PCSK9 in the CCD, followed by elevated plasma levels and worsening hypercholesterolemia. Thus, our data suggest that PCSK9 in the kidney plays a role in the initiation of hypercholesterolemia in nephrotic syndrome and make a case for depletion of PCSK9 early in patients with nephrotic syndrome to prevent the development of hypercholesterolemia.
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