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Recombinant N-Terminal Slit2 Inhibits TGF-?-Induced Fibroblast Activation and Renal Fibrosis.


ABSTRACT: Fibrosis and inflammation are closely intertwined injury pathways present in nearly all forms of CKD for which few safe and effective therapies exist. Slit glycoproteins signaling through Roundabout (Robo) receptors have been described to have anti-inflammatory effects through regulation of leukocyte cytoskeletal organization. Notably, cytoskeletal reorganization is also required for fibroblast responses to TGF-? Here, we examined whether Slit2 also controls TGF-?-induced renal fibrosis. In cultured renal fibroblasts, which we found to express Slit2 and Robo-1, the bioactive N-terminal fragment of Slit2 inhibited TGF-?-induced collagen synthesis, actin cytoskeletal reorganization, and Smad2/3 transcriptional activity, but the inactive C-terminal fragment of Slit2 did not. In mouse models of postischemic renal fibrosis and obstructive uropathy, treatment with N-terminal Slit2 before or after injury inhibited the development of renal fibrosis and preserved renal function, whereas the C-terminal Slit2 had no effect. Our data suggest that administration of recombinant Slit2 may be a new treatment strategy to arrest chronic injury progression after ischemic and obstructive renal insults by not only attenuating inflammation but also, directly inhibiting renal fibrosis.

SUBMITTER: Yuen DA 

PROVIDER: S-EPMC5004640 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Recombinant N-Terminal Slit2 Inhibits TGF-β-Induced Fibroblast Activation and Renal Fibrosis.

Yuen Darren A DA   Huang Yi-Wei YW   Liu Guang-Ying GY   Patel Sajedabanu S   Fang Fei F   Zhou Joyce J   Thai Kerri K   Sidiqi Ahmad A   Szeto Stephen G SG   Chan Lauren L   Lu Mingliang M   He Xiaolin X   John Rohan R   Gilbert Richard E RE   Scholey James W JW   Robinson Lisa A LA  

Journal of the American Society of Nephrology : JASN 20160211 9


Fibrosis and inflammation are closely intertwined injury pathways present in nearly all forms of CKD for which few safe and effective therapies exist. Slit glycoproteins signaling through Roundabout (Robo) receptors have been described to have anti-inflammatory effects through regulation of leukocyte cytoskeletal organization. Notably, cytoskeletal reorganization is also required for fibroblast responses to TGF-β Here, we examined whether Slit2 also controls TGF-β-induced renal fibrosis. In cult  ...[more]

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