Associations of urinary polymeric immunoglobulin receptor peptides in the context of cardio-renal syndrome

Abstract

the polymeric immunoglobulin receptor (pigR) transports immunoglobulins from the basolateral to the apical surface of epithelial cells. PIgR was recently shown to be associated with kidney dysfunction. the immune defense is initiated at the apical surface of epithelial cells where the n-terminal domain of pIgR, termed secretory component (SC), is proteolytically cleaved and released either unbound (free SC) or bound to immunoglobulins. The aim of our study was to evaluate the association of pIgR peptides with the cardio-renal syndrome in a large cohort and to obtain information on how the Sc is released. We investigated urinary peptides of 2964 individuals available in the Human Urine Proteome Database generated using capillary electrophoresis coupled to mass spectrometry. The mean amplitude of 23 different pIgR peptides correlated negatively with the estimated glomerular filtration rate (eGFR, rho = −0.309, p < 0.0001). Furthermore, pIgR peptides were significantly increased in cardiovascular disease (coronary artery disease and heart failure) after adjustment for eGFR. We further predicted potential proteases involved in urinary peptide generation using the Proteasix algorithm. Peptide cleavage site analysis suggested that several, and not one, proteases are involved in the generation of the SC. In this large cohort, we could demonstrate that pIgR is associated with the cardio-renal syndrome and provided a more detailed insight on how pIgR can be potentially cleaved to release the SC.

Role of Polymeric Immunoglobulin Receptor in IgA and IgM Transcytosis

“…The cysteine residues in the extracellular portion, from which disulfide bonds may form, are conserved among human, mouse, rat and a few other mammalian species [ 11 ]. Domain 6, which is closest to the transmembrane portion, contains a highly conserved proteolytic cleavage site [ 12 ]. Compared to the extracellular portion, the intracellular portion of pIgR is more directly involved in intracellular sorting, endocytosis and transcytosis [ 13 ] ( Figure 1 ).…”

Urine peptidome analysis in cardiorenal syndrome reflects molecular processes

“…These proteins were CD14 (a protein which is associated with heart and renal dysfunction 49 ), CD99 and IRF6, suggesting the importance of the immune response in CRS. In addition, urinary PIGR peptides have been previously associated with cardiorenal dysfunction 50 , nevertheless, the exact role of the protein in the disease pathology remains unknown.…”

Urinary Protein and Peptide Markers in Chronic Kidney Disease

“…Harald Mischak's group is the leader in MS studies on the urinary peptidome and proteome. This group described 1580 native urinary peptides, showing that 73% were unique for urine and proving the clinical value of native urinary peptide markers for diagnosing several diseases, including those associated with kidney damage [14,77,78].…”