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

Tianlin He,Harald Mischak,Petra Zürbig,Vera Jankowski,Joost P Schanstra,William Mullen,Jochen Metzger,Justyna Siwy

doi:10.1038/s41598-020-65154-2

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.

Highlights

The polymeric immunoglobulin receptor transports immunoglobulins from the basolateral to the apical surface of epithelial cells
We could further confirm the findings reported by Krawczyk et al that the polymeric immunoglobulin receptor (pIgR) amplitude is lower in the urine of minimal change disease (MCD) patients than it is in healthy controls
Some pIgR peptides are included in the peptide-based classifier CKD273 which was proven in several studies to have a high accuracy in the early diagnosis and the prediction of chronic kidney disease (CKD) progression[13,14]

Summary

Introduction

The polymeric immunoglobulin receptor (pIgR) transports immunoglobulins from the basolateral to the apical surface of epithelial cells. 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. 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. They were able to show that human pIgR is expressed in proximal tubules and glomeruli They demonstrated that during chronic kidney disease (CKD) the expression of pIgR in the tubules becomes prevalent, associated with increased levels of urinary secretory immunoglobulins. Elevated levels of total serum IgA have been reported in patients with severe atherosclerosis or with previous myocardial infarction or other major ischemic events[9,10]

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