Journal Article

Circulating testican-2 is a podocyte-derived marker of kidney health

Katz, Dan H., Vasan, Ramachandran S., Wilson, James G., Wang, Thomas J., Elmariah, Sammy, Sinha, Sumita, Yang, Qiong, Correa, Adolfo, Young, Bessie A., Pollak, Martin R., Wen, Donghai, Keyes, Michelle J., Friedman, David J., Smith, J. Gustav, Gerszten, Robert E., Larson, Martin G., Ngo, Debby, Gao, Yan, Drury, Erika R., Benson, Mark D., Humphreys, Benjamin D., Shen, Dongxiao, Peterson, Bennet D., Rhee, Eugene P., Farrell, Laurie A.

2020

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Aptamers / Aptamers, Peptide / Biological Sciences / Biomarkers / Biomarkers - metabolism / Black or African American - genetics / Body mass index / Body size / Clinical Medicine / Diabetes mellitus (non-insulin dependent) / Electron microscopy / Epidermal growth factor receptors / Female / Gene expression / Gene sequencing / Glomerular filtration rate / Glomerular Filtration Rate - genetics / Glomerulus / Humans / Hypertension / Hypertension - genetics / Hypertension - pathology / Immunofluorescence / Immunohistochemistry / Kidney - metabolism / Kidney - pathology / Kidney Function Tests / Kidney Glomerulus - metabolism / Kidneys / Klinisk medicin / Male / Medical and Health Sciences / Medical Sciences / Medicin och hälsovetenskap / Middle Aged / Podocytes - metabolism / Podocytes - pathology / Proteins / Proteoglycans - genetics / Proteoglycans - metabolism / Proteomics / Ribonucleic acid / RNA