suPAR: An Inflammatory Mediator for Kidneys

Abstract

Background: Inflammation is a common feature of many kidney diseases. The implicated inflammatory mediators and their underlying molecular mechanisms however are often not clear.

Summary: suPAR is the soluble form of urokinase-type plasminogen activator receptor (uPAR), associated with inflammation and immune activation. It has evolved into a unique circulating kidney disease factor over the last 10 years. In particular, suPAR has multiple looks due to enzymatic cleavage and alternative transcriptional splicing of the uPAR gene. Most recently, suPAR has emerged as a systemic mediator for COVID-19 infection, associated with lung as well as kidney dysfunction. Like membrane-bound uPAR, suPAR could interact with integrins (e.g., αvβ3 integrin) on podocytes, providing the molecular basis for some glomerular kidney diseases. In addition, there have been numerous studies suggesting that suPAR connects acute kidney injury to chronic kidney disease as a special kidney risk factor. Moreover, the implication of circulating suPAR levels in kidney transplantation and plasmapheresis not only indicates its relevance in monitoring for recurrence but also implies suPAR as a possible therapeutic target. In fact, the therapeutic concept of manipulating suPAR function has been evidenced in several kidney disease experimental models.

Key messages: The last 10 years of research has established suPAR as a unique inflammatory mediator for kidneys. While open questions remain and deserve additional studies, modulating suPAR function may represent a promising novel therapeutic strategy for kidney disease.

Keywords: Biomarker; COVID-19; Integrin; Kidney; Soluble urokinase-type plasminogen activator receptor; Therapeutics.

Fig. 1

suPAR and the kidney − an evolving story. Membrane-bound uPAR (e.g., podocyte uPAR) could mediate cell signaling in an “autocrine” or “paracrine” manner. uPAR has multiple isoforms due to alternative transcription. Cleavage of the GPI anchor from the cell membrane or direct secretion from cells generates suPAR that circulates in blood. Infection and/or inflammation such as COVID-19 promotes suPAR production from bone marrow myeloid cells. High circulating suPAR levels are associated with both AKI and CKD as a kidney disease factor. In certain circumstance, suPAR alone (i.e., dimerized form) or together with other risk factors (such as CD40 autoantibody, or APOL1 risk variants) causes FSGS-like changes.