uPAR isoform 2 forms a dimer and induces severe kidney disease in mice.

Autor:	Wei C; Department of Medicine, Rush University Medical Center, Chicago, Illinois, USA., Li J; Department of Medicine, Rush University Medical Center, Chicago, Illinois, USA., Adair BD; Harvard Medical School, Division of Nephrology, Massachusetts General Hospital, Charlestown, Massachusetts, USA., Zhu K; Department of Medicine, Rush University Medical Center, Chicago, Illinois, USA., Cai J; University of Louisville, Louisville, Kentucky, USA., Merchant M; University of Louisville, Louisville, Kentucky, USA., Samelko B; Department of Medicine, Rush University Medical Center, Chicago, Illinois, USA., Liao Z; Department of Medicine, UCSD, La Jolla, California, USA., Koh KH; Department of Medicine, Rush University Medical Center, Chicago, Illinois, USA., Tardi NJ; Department of Medicine, Rush University Medical Center, Chicago, Illinois, USA., Dande RR; Department of Medicine, Rush University Medical Center, Chicago, Illinois, USA., Liu S; Department of Medicine, Rush University Medical Center, Chicago, Illinois, USA., Ma J; Department of Medicine, Rush University Medical Center, Chicago, Illinois, USA., Dibartolo S; Department of Medicine, Rush University Medical Center, Chicago, Illinois, USA., Hägele S; Department of Medicine, Rush University Medical Center, Chicago, Illinois, USA., Peev V; Department of Medicine, Rush University Medical Center, Chicago, Illinois, USA., Hayek SS; University of Michigan Frankel Cardiovascular Center, Ann Arbor, Michigan, USA., Cimbaluk DJ; Department of Pathology, Rush University Medical Center, Chicago, Illinois, USA., Tracy M; Department of Medicine, Rush University Medical Center, Chicago, Illinois, USA., Klein J; University of Louisville, Louisville, Kentucky, USA., Sever S; Harvard Medical School, Division of Nephrology, Massachusetts General Hospital, Charlestown, Massachusetts, USA., Shattil SJ; Department of Medicine, UCSD, La Jolla, California, USA., Arnaout MA; Harvard Medical School, Division of Nephrology, Massachusetts General Hospital, Charlestown, Massachusetts, USA., Reiser J; Department of Medicine, Rush University Medical Center, Chicago, Illinois, USA.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2019 Apr 02; Vol. 129 (5), pp. 1946-1959. Date of Electronic Publication: 2019 Apr 02 (Print Publication: 2019).
DOI:	10.1172/JCI124793
Abstrakt:	Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived circulating signaling molecule that has been implicated in chronic kidney disease, such as focal segmental glomerulosclerosis (FSGS). Typically, native uPAR (isoform 1) translates to a 3-domain protein capable of binding and activating integrins, yet the function of additional isoforms generated by alternative splicing is unknown. Here, we characterized mouse uPAR isoform 2 (msuPAR2), encoding domain I and nearly one-half of domain II, as a dimer in solution, as revealed by 3D electron microscopy structural analysis. In vivo, msuPAR2 transgenic mice exhibited signs of severe renal disease characteristic of FSGS with proteinuria, loss of kidney function, and glomerulosclerosis. Sequencing of the glomerular RNAs from msuPAR2-Tg mice revealed a differentially expressed gene signature that includes upregulation of the suPAR receptor Itgb3, encoding β3 integrin. Crossing msuPAR2-transgenic mice with 3 different integrin β3 deficiency models rescued msuPAR2-mediated kidney function. Further analyses indicated a central role for β3 integrin and c-Src in msuPAR2 signaling and in human FSGS kidney biopsies. Administration of Src inhibitors reduced proteinuria in msuPAR2-transgenic mice. In conclusion, msuPAR2 may play an important role in certain forms of scarring kidney disease.
Databáze:	MEDLINE
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