Thrombospondin-1 deficiency causes a shift from fibroproliferative to inflammatory kidney disease and delays onset of renal failure

Michael Zeisberg, Björn Tampe, Valerie Lebleu, Desiree Tampe, Elisabeth M. Zeisberg, Raghu Kalluri

Research output: Contribution to journalArticle

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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 levele 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-b1 (TGF-b1) 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-b1, 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.

Original languageEnglish (US)
Pages (from-to)2687-2698
Number of pages12
JournalAmerican Journal of Pathology
Volume184
Issue number10
DOIs
StatePublished - Jan 1 2014

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Thrombospondin 1
Kidney Diseases
Renal Insufficiency
Knockout Mice
Kidney
Chronic Renal Insufficiency
Transforming Growth Factors
Disease Progression
Collagen
Chronic Kidney Failure
Creatinine
Fibroblasts
Inflammation
Proteins

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Thrombospondin-1 deficiency causes a shift from fibroproliferative to inflammatory kidney disease and delays onset of renal failure. / Zeisberg, Michael; Tampe, Björn; Lebleu, Valerie; Tampe, Desiree; Zeisberg, Elisabeth M.; Kalluri, Raghu.

In: American Journal of Pathology, Vol. 184, No. 10, 01.01.2014, p. 2687-2698.

Research output: Contribution to journalArticle

Zeisberg, Michael ; Tampe, Björn ; Lebleu, Valerie ; Tampe, Desiree ; Zeisberg, Elisabeth M. ; Kalluri, Raghu. / Thrombospondin-1 deficiency causes a shift from fibroproliferative to inflammatory kidney disease and delays onset of renal failure. In: American Journal of Pathology. 2014 ; Vol. 184, No. 10. pp. 2687-2698.
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