title: Thrombospondin-1 deficiency causes a shift from fibroproliferative to inflammatory kidney disease and delays onset of renal failure.
abstract: Thrombospondin-1 (TSP1) is a multifunctional matricellular protein known to promote progression of chronic kidney disease. To gain insight into the underlying mechanisms through which TSP1 accelerates chronic kidney disease, we compared disease progression in Col4a3 knockout (KO) mice, which develop spontaneous kidney failure, with that of Col4a3;Tsp1 double-knockout (DKO) mice. Decline of excretory renal function was significantly delayed in the absence of TSP1. Although Col4a3;Tsp1 DKO mice did progress toward end-stage renal failure, their kidneys exhibited distinct histopathological lesions, compared with creatinine level-matched Col4a3 KO mice. Although kidneys of both Col4a3 KO and Col4a3;Tsp1 DKO mice exhibited a widened tubulointerstitium, predominant lesions in Col4a3 KO kidneys were collagen deposition and fibroblast accumulation, whereas in Col4a3;Tsp1 DKO kidney inflammation was predominant, with less collagen deposition. Altered disease progression correlated with impaired activation of transforming growth factor-β1 (TGF-β1) in vivo and in vitro in the absence of TSP1. In summary, our findings suggest that TSP1 contributes to progression of chronic kidney disease by catalyzing activation of latent TGF-β1, resulting in promotion of a fibroproliferative response over an inflammatory response. Furthermore, the findings suggest that fibroproliferative and inflammatory lesions are independent entities, both of which contribute to decline of renal function.
authors.affiliation: Department of Nephrology and Rheumatology, Göttingen University Medical Center, Georg August University, Göttingen, Germany; Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. Electronic address: mzeisberg@med.uni-goettingen.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Zeisberg
authors.affiliation: Department of Nephrology and Rheumatology, Göttingen University Medical Center, Georg August University, Göttingen, Germany; Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Björn
authors.initials: B
authors.lastname: Tampe
authors.affiliation: Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; Department of Cancer Biology and the Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Valerie
authors.initials: V
authors.lastname: LeBleu
authors.affiliation: Department of Nephrology and Rheumatology, Göttingen University Medical Center, Georg August University, Göttingen, Germany; Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Desiree
authors.initials: D
authors.lastname: Tampe
authors.affiliation: Department of Cardiology and Pneumology, Göttingen University Medical Center, Georg August University, Göttingen, Germany; Department of Cancer Biology and the Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas; German Center for Cardiovascular Research (DZHK), Göttingen, Germany.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Zeisberg
authors.affiliation: Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; Department of Cancer Biology and the Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address: rkalluri@mdanderson.org.
authors.forename: Raghu
authors.initials: R
authors.lastname: Kalluri
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000378:metabolism; D024141:Collagen Type IV / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D018450:Disease Progression; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology*; D007668:Kidney / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009393:Nephritis; D051437:Renal Insufficiency / Q000378:metabolism / Q000473:pathology*; D019700:Thrombospondin 1 / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D001324:Autoantigens; D024141:Collagen Type IV; D019700:Thrombospondin 1; D053773:Transforming Growth Factor beta1; C585483:Thbs1 protein, mouse; C057112:type IV collagen alpha3 chain; D003404:Creatinine
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