{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T11:27:47Z","timestamp":1790681267122,"version":"4.1.0"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2016,7,5]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>In nephrotic syndrome, damage to the podocytes of the kidney produces severe hypercholesterolemia for which novel treatments are urgently needed. PCSK9 (proprotein convertase subtilisin\/kexin type 9) has emerged as an important regulator of plasma cholesterol levels and therapeutic target. Here, we tested the role of PCSK9 in mediating the hypercholesterolemia of nephrotic syndrome.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              PCSK9 and plasma lipids were studied in nephrotic syndrome patients before and after remission of disease, mice with genetic ablation of the podocyte (Podocyte Apoptosis Through Targeted Activation of Caspase-8, Pod-ATTAC mice) and mice treated with nephrotoxic serum (NTS), which triggers immune-mediated podocyte damage. In addition, mice with hepatic deletion of\n              <jats:italic>Pcsk9<\/jats:italic>\n              were treated with NTS to determine the contribution of PCSK9 to the dyslipidemia of nephrotic syndrome.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              Patients with nephrotic syndrome showed a decrease in plasma cholesterol and plasma PCSK9 on remission of their disease (\n              <jats:italic>P<\/jats:italic>\n              &lt;0.05, n=47\u201350). Conversely, Pod-ATTAC mice and NTS-treated mice showed hypercholesterolemia and a 7- to 24-fold induction in plasma PCSK9. The induction of plasma PCSK9 appeared to be attributable to increased secretion of PCSK9 from the hepatocyte coupled with decreased clearance. Interestingly, knockout of\n              <jats:italic>Pcsk9<\/jats:italic>\n              ameliorated the effects of NTS on plasma lipids. Thus, in the presence of NTS, mice lacking hepatic\n              <jats:italic>Pcsk9<\/jats:italic>\n              showed a 40% to 50% decrease in plasma cholesterol and triglycerides. Moreover, the ability of NTS treatment to increase the percentage of low-density lipoprotein\u2013associated cholesterol (from 9% in vehicle-treated Flox mice to 47% after NTS treatment), was lost in mice with hepatic deletion of\n              <jats:italic>Pcsk9<\/jats:italic>\n              (5% in both the presence and absence of NTS).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              Podocyte damage triggers marked inductions in plasma PCSK9, and knockout of\n              <jats:italic>Pcsk9<\/jats:italic>\n              ameliorates dyslipidemia in a mouse model of nephrotic syndrome. These data suggest that PCSK9 inhibitors may be beneficial in patients with nephrotic syndrome\u2013associated hypercholesterolemia.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.115.020912","type":"journal-article","created":{"date-parts":[[2016,6,29]],"date-time":"2016-06-29T23:19:21Z","timestamp":1467242361000},"page":"61-72","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":104,"title":["The Role of Proprotein Convertase Subtilisin\/Kexin Type 9 in Nephrotic Syndrome-Associated Hypercholesterolemia"],"prefix":"10.1161","volume":"134","author":[{"given":"Mary E.","family":"Haas","sequence":"first","affiliation":[{"name":"From Division of Endocrinology, Boston Children\u2019s Hospital; Department of Pediatrics, Harvard Medical School, MA (M.E.H., A.E.L., X.S., W.-H.L., S.B.B.); Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas (J.M.R., P.E.S.); Division of Cardiology, Boston Children\u2019s Hospital; Department of Pediatrics, Harvard Medical School, MA (S.D.d.F.); Division of Nephrology, Boston Children\u2019s Hospital, Department of Pediatrics,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy E.","family":"Levenson","sequence":"additional","affiliation":[{"name":"From Division of Endocrinology, Boston Children\u2019s Hospital; Department of Pediatrics, Harvard Medical School, MA (M.E.H., A.E.L., X.S., W.-H.L., S.B.B.); Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas (J.M.R., P.E.S.); Division of Cardiology, Boston Children\u2019s Hospital; Department of Pediatrics, Harvard Medical School, MA (S.D.d.F.); Division of Nephrology, Boston Children\u2019s Hospital, Department of Pediatrics,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowei","family":"Sun","sequence":"additional","affiliation":[{"name":"From Division of Endocrinology, Boston Children\u2019s Hospital; Department of Pediatrics, Harvard Medical School, MA (M.E.H., A.E.L., X.S., W.-H.L., S.B.B.); Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas (J.M.R., P.E.S.); Division of Cardiology, Boston Children\u2019s Hospital; Department of Pediatrics, Harvard Medical School, MA (S.D.d.F.); Division of Nephrology, Boston Children\u2019s Hospital, Department of Pediatrics,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan-Hui","family":"Liao","sequence":"additional","affiliation":[{"name":"From Division of Endocrinology, Boston Children\u2019s Hospital; Department of Pediatrics, Harvard Medical School, MA (M.E.H., A.E.L., X.S., W.-H.L., S.B.B.); Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas (J.M.R., P.E.S.); Division of Cardiology, Boston Children\u2019s Hospital; Department of Pediatrics, Harvard Medical School, MA (S.D.d.F.); Division of Nephrology, Boston Children\u2019s Hospital, Department of Pediatrics,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph M.","family":"Rutkowski","sequence":"additional","affiliation":[{"name":"From Division of Endocrinology, Boston Children\u2019s Hospital; Department of Pediatrics, Harvard Medical School, MA (M.E.H., A.E.L., X.S., W.-H.L., S.B.B.); Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas (J.M.R., P.E.S.); Division of Cardiology, Boston Children\u2019s Hospital; Department of Pediatrics, Harvard Medical School, MA (S.D.d.F.); Division of Nephrology, Boston Children\u2019s Hospital, Department of Pediatrics,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Nephrotic Syndrome Study Network","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah D.","family":"de Ferranti","sequence":"additional","affiliation":[{"name":"From Division of Endocrinology, Boston Children\u2019s Hospital; Department of Pediatrics, Harvard Medical School, MA (M.E.H., A.E.L., X.S., W.-H.L., S.B.B.); Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas (J.M.R., P.E.S.); Division of Cardiology, Boston Children\u2019s Hospital; Department of Pediatrics, Harvard Medical School, MA (S.D.d.F.); Division of Nephrology, Boston Children\u2019s Hospital, Department of Pediatrics,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie A.","family":"Schumacher","sequence":"additional","affiliation":[{"name":"From Division of Endocrinology, Boston Children\u2019s Hospital; Department of Pediatrics, Harvard Medical School, MA (M.E.H., A.E.L., X.S., W.-H.L., S.B.B.); Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas (J.M.R., P.E.S.); Division of Cardiology, Boston Children\u2019s Hospital; Department of Pediatrics, Harvard Medical School, MA (S.D.d.F.); Division of Nephrology, Boston Children\u2019s Hospital, Department of Pediatrics,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp E.","family":"Scherer","sequence":"additional","affiliation":[{"name":"From Division of Endocrinology, Boston Children\u2019s Hospital; Department of Pediatrics, Harvard Medical School, MA (M.E.H., A.E.L., X.S., W.-H.L., S.B.B.); Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas (J.M.R., P.E.S.); Division of Cardiology, Boston Children\u2019s Hospital; Department of Pediatrics, Harvard Medical School, MA (S.D.d.F.); Division of Nephrology, Boston Children\u2019s Hospital, Department of Pediatrics,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Salant","sequence":"additional","affiliation":[{"name":"From Division of Endocrinology, Boston Children\u2019s Hospital; Department of Pediatrics, Harvard Medical School, MA (M.E.H., A.E.L., X.S., W.-H.L., S.B.B.); Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas (J.M.R., P.E.S.); Division of Cardiology, Boston Children\u2019s Hospital; Department of Pediatrics, Harvard Medical School, MA (S.D.d.F.); Division of Nephrology, Boston Children\u2019s Hospital, Department of Pediatrics,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sudha B.","family":"Biddinger","sequence":"additional","affiliation":[{"name":"From Division of Endocrinology, Boston Children\u2019s Hospital; Department of Pediatrics, Harvard Medical School, MA (M.E.H., A.E.L., X.S., W.-H.L., S.B.B.); Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas (J.M.R., P.E.S.); Division of Cardiology, Boston Children\u2019s Hospital; Department of Pediatrics, Harvard Medical School, MA (S.D.d.F.); Division of Nephrology, Boston Children\u2019s Hospital, Department of Pediatrics,..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","first-page":"274","article-title":"On the cause of the milky and whey-like appearances sometimes observed in the blood.","volume":"33","author":"Christison R","year":"1830","unstructured":"Christison R. 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