The role of suPAR and related proteins in kidney, heart diseases, and diabetes
Jochen Reiser, Salim S. Hayek, Sanja Sever
Jochen Reiser, Salim S. Hayek, Sanja Sever
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Review Cardiology Immunology Nephrology

The role of suPAR and related proteins in kidney, heart diseases, and diabetes

Abstract

The urokinase plasminogen activator receptor (uPAR) is a membrane-bound protein found on the surface of immune cells. Through the action of proteases, uPAR is cleaved to produce several circulating proteins in the bloodstream, including the soluble form suPAR and the fragments D1 and D2D3. Initially studied in the context of infectious diseases and cancer, recent research has revealed roles for suPAR and its related proteins as mediators linking innate immunity to the pathogenesis of kidney and cardiovascular diseases, as well as insulin-dependent diabetes. While these proteins have long been recognized as prognostic biomarkers, growing clinical, experimental, and genetic evidence highlights their active involvement in the onset and progression of these diverse conditions. This Review examines suPAR’s evolution from its discovery as a modulator of innate immunity to its current status as a key driver in chronic kidney and cardiovascular diseases. Furthermore, we explore the molecular mechanisms through which suPAR and D2D3 contribute to multiorgan damage, emphasizing emerging opportunities for therapeutic interventions across interconnected organ systems.

Authors

Jochen Reiser, Salim S. Hayek, Sanja Sever

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Figure 2

uPAR and its associated proteins engage in a variety of protein-protein interactions.

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uPAR and its associated proteins engage in a variety of protein-protein ...
(A) Interactions with integrin: Downstream pathways activated by interactions between integrins and uPAR or its related proteins, suPAR and D2D3, across different cell types. All structural models were generated using AlphaFold version 2 (111). UniProt numbers: UPAR_HUMAN (Q03405), ITAV_HUMAN (P06756), and ITB3_HUMAN (P05106). suPAR and αvβ3 integrin on podocytes: The activation of αvβ3 integrin on podocytes by uPAR and suPAR has been proposed as a mechanism contributing to podocyte injury. suPAR and αMβ2 on macrophages and neutrophils: uPAR binding to αMβ2 integrin facilitates the adhesion of macrophages and neutrophils to ECM components and endothelial cells. uPAR/suPAR and αMβ2 integrin interactions influence cytoskeletal rearrangements and reactive oxygen species (ROS) production in those cells. suPAR and α3β1 integrin on cancer cells (breast, prostate, and lung): While direct interactions between uPAR and the β1 integrin subunit have been observed in various cell types, such as fibroblasts, macrophages, and monocytes, this interaction is particularly well studied in cancer cells. In this context, direct uPAR–α3β1 integrin interactions play a critical role in promoting tumor cell migration, invasion, and metastasis. (B) Suggested interactions between uPAR/suPAR and diverse proteins: Computer models were generated using AlphaFold version 2 (111) and protein information from UniProt (https://www.uniprot.org/). uPAR and uPA UniProt numbers: UPAR_HUMAN (Q03405) and UROK_HUMAN (P00749). When uPA binds to membrane-associated uPAR, it forms a complex that facilitates the conversion of plasminogen to plasmin. Moreover, uPA can cleave uPAR itself, resulting in the release of suPAR from the cell surface. suPAR and TNFRSF19 UniProt numbers: UPAR_HUMAN (Q03405) and TNR19_HUMAN (Q9NS68). TNFRSF19 is a TNF receptor superfamily member, a transmembrane protein implicated in inhibiting the TGF-β signaling pathway. suPAR and ApoL1 UniProt numbers: UPAR_HUMAN (Q03405) and APOL1_HUMAN (O14791). This interaction has been implicated in inducing chronic kidney diseases, particularly in individuals of recent African ancestry.