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c-Src is in the effector pathway linking uPAR and podocyte injury
Jeffrey B. Kopp, Jurgen Heymann
Jeffrey B. Kopp, Jurgen Heymann
Published April 2, 2019
Citation Information: J Clin Invest. 2019;129(5):1827-1829. https://doi.org/10.1172/JCI127927.
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Commentary

c-Src is in the effector pathway linking uPAR and podocyte injury

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Abstract

The role of urokinase-type plasminogen activator receptor (uPAR) in kidney physiology and pathology has attracted considerable attention. The protein uPAR has dual functions: as a key regulator of plasmin generation and a component of the innate immune system. In the current issue, Wei and colleagues describe a transgenic mouse expressing Plaur RNA in glomerular podocytes. The mice manifested podocyte injury, including c-Src phosphorylation, proteinuria, and focal segmental glomerulosclerosis (FSGS). Plaur-transgenic mice on a β3 integrin–deficient background were protected from podocyte injury. Renal biopsies from subjects with FSGS, but not those with other glomerular diseases, manifested increased c-Src phosphorylation in podocytes. These findings suggest a novel injury mechanism in FSGS, with possible implications for new treatment strategies.

Authors

Jeffrey B. Kopp, Jurgen Heymann

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Figure 1

Mechanism of uPAR in podocyte injury.

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Mechanism of uPAR in podocyte injury.
Mus musculus (MM) uPAR1 isoform 1 ...
Mus musculus (MM) uPAR1 isoform 1 is secreted and anchored to the plasma membrane via the GPI anchor, and is then converted from a membrane-bound form (uPAR) into a soluble form (suPAR) by enzymatic removal of the GPI anchor. MM uPAR isoform 2 lacks a GPI anchor and hence is a suPAR; in contrast to MM isoform 1, it forms a soluble dimer. In mice transgenic for either MM isoform 1 or MM isoform 2, suPAR binds avβ3 integrin located at the podocyte foot process plasma membrane. Binding of suPAR isoform 2, possibly as a dimer, generates phosphorylated c-Src, through outside-in signaling. By contrast, for isoform 1, no c-Src-P was detected. Transgenic mice bearing suPAR isoform 2 uniquely develop proteinuria and glomerulosclerosis. Targeting of c-Src with Src-specific inhibitors (Src inhibitor 1 or PP1) reduced proteinuria. Homo sapiens (HS) uPAR isoform 3 is the result of in-frame exon splicing leading to preservation of the GPI anchor and is predicted to form dimers, resembling MM isoform 2. Elevated levels of phosphorylated c-Src were found in human kidney biopsy samples, as with MM suPAR isoform 2 mice. This suggests that in human podocytes HS suPAR isoform 3 functions similarly to MM isoform 2, increasing phosphorylated c-Src, which drives the development of FSGS. D, domain. D2*, truncated D2.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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