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

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.

Plasma Proteomics of Renal Function: A Transethnic Meta-Analysis and Mendelian Randomization Study

“…Additional analyses in the discovery cohort produced associations between eGFR decline and DAN, TNF sR-1 and FSTL3, in line with those previously reported. 18 No overlap between the set of proteins associated with uACR and the proteins previously reported 73 was observed, which may be explained by the different time points of the eGFR and albuminuria measurements. 73 No proteins were significantly associated with MA, possibly due to its low prevalence (5.9%) in KORA.…”

“…Low plasma levels of testican-2 may be indicative of poor renal function, meaning this protein may be a physiological biomarker of kidney health and disease progression. 17,18 Although the reverse direction of this causal association did not reach statistical significance in our MR analyses, a reverse causal effect (i.e., testican-2 on renal function) is biologically plausible given the role matricellular proteins play in extracellular matrix repair 83,90 and its in vitro effects on human glomerular endothelial cells. 18 The utility of testican-2 as a biomarker with regard to its potential functional effects, tissue of origin, or the mechanisms influencing its blood levels, requires further study.…”

“…18 Its protein-coding gene, SPOCK2, is associated with both normal maintenance of organ and tissue integrity, and with wound healing and other responses to injury. 85 Despite the ubiquitous expression of this gene, its enriched expression in human glomeruli in comparison to other nonrenal tissues 18,[86][87][88][89] and its renal downregulation in diabetic kidney disease 86 suggest it has a particularly relevant role in renal cellular mechanisms. Furthermore, recent evidence from arteriovenous sampling demonstrated renal release of this protein into the bloodstream, 18 which in addition to its urine detection, 84 suggests changes in its plasma levels may be indicative of kidney function.…”

Proteomics and Population Biology in the Cardiovascular Health Study (CHS): design of a study with mentored access and active data sharing

“…The CHS Proteomics study has good power for association with a variety of outcomes. Investigators from the Framingham Heart Study (FHS) and the Jackson Heart Study (JHS), both of which have SomaLogic data and have subcontracts for replication and collaborative meta-analyses [ 48 , 49 ], are active collaborators. Additionally, we are actively seeking collaboration with other national and international studies that have proteomic data to improve power.…”

Glomerular Endothelial Cell Crosstalk With Podocytes in Diabetic Kidney Disease

“…In recent work, Ngo et al collected plasma samples to assess renal arteriovenous gradients ( 77 ). A positive correlation between testican-2 and eGFR, and an association between higher baseline testican-2 levels and slower decline of eGFR, were observed in cohorts of patients including diabetics.…”