한빛사 논문
Debby Ngoa,b,1, Donghai Wenc,d,1, Yan Gaoe, Michelle J. Keyesa, Erika R. Druryf, Dan H. Katza, Mark D. Bensona, Sumita Sinhaa, Dongxiao Shena, Laurie A. Farrella, Bennet D. Petersona, David J. Friedmang, Sammy Elmariahh, Bessie A. Youngi,j, J. Gustav Smithk,l,m, Qiong Yangn, Ramachandran S. Vasano,p,q, Martin G. Larsonn,q, Adolfo Correae, Benjamin D. Humphreysr, Thomas J. Wangs, Martin R. Pollakg,2, James G. Wilsona, Robert E. Gersztena, and Eugene P. Rheec,d,2
aDivision of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215; bDivision of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215; cNephrology Division, Massachusetts General Hospital, Boston, MA 02114; dEndocrine Unit, Massachusetts General Hospital, Boston, MA 02114; eJackson Heart Study, Department of Medicine, University of Mississippi, Jackson, MS 39216; fDivision of Nephrology, University of Rochester School of Medicine, Rochester, NY 14642; gDivision of Nephrology, Beth Israel Deaconess Medical Center, Boston, MA 02215; hCardiology Division, Massachusetts General Hospital, Boston, MA 02114; iKidney Research Institute, University of Washington, Seattle, WA 98104; jDivision of Nephrology, Veteran Affairs Puget Sound Healthcare, Seattle, WA 98108; kDepartment of Cardiology, Clinical Sciences, Lund University and Skåne University Hospital, 221 84 Lund, Sweden; lDepartment of Cardiology, Gothenburg University and Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden; mWallenberg Laboratory, Gothenburg University and Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden; nDepartment of Biostatistics, Boston University School of Public Health, Boston, MA 02118; oDivision of Preventive Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA 02118; pDivision of Cardiology, Department of Medicine, Boston University School of Medicine, Boston, MA 02118; qThe Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA 01702; rDivision of Nephrology, Washington University of St. Louis School of Medicine, St. Louis, MO 63110; and sDepartment of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390
1D.N. and D.W. contributed equally to this work.
2To whom correspondence may be addressed.
Abstract
In addition to their fundamental role in clearance, the kidneys release select molecules into the circulation, but whether any of these anabolic functions provides insight on kidney health is unknown. Using aptamer-based proteomics, we characterized arterial (A)-to-renal venous (V) gradients for >1,300 proteins in 22 individuals who underwent invasive sampling. Although most of the proteins that changed significantly decreased from A to V, consistent with renal clearance, several were found to increase, the most significant of which was testican-2. To assess the clinical implications of these physiologic findings, we examined proteomic data in the Jackson Heart Study (JHS), an African-American cohort (n = 1,928), with replication in the Framingham Heart Study (FHS), a White cohort (n = 1,621). In both populations, testican-2 had a strong, positive correlation with estimated glomerular filtration rate (eGFR). In addition, higher baseline testican-2 levels were associated with a lower rate of eGFR decline in models adjusted for age, gender, hypertension, type 2 diabetes, body mass index, baseline eGFR, and albuminuria. Glomerular expression of testican-2 in human kidneys was demonstrated by immunohistochemistry, immunofluorescence, and electron microscopy, while single-cell RNA sequencing of human kidneys showed expression of the cognate gene, SPOCK2, exclusively in podocytes. In vitro, testican-2 increased glomerular endothelial tube formation and motility, raising the possibility that its secretion has a functional role within the glomerulus. Taken together, our findings identify testican-2 as a podocyte-derived biomarker of kidney health and prognosis.
testican-2, proteomics, chronic kidney disease
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