Leptospiral outer membrane protein induces extracellular matrix accumulation through a TGF-beta1/Smad-dependent pathway.
Leptospirosis is an underestimated cause of renal failure in Taiwan and elsewhere. The consequence of leptospira-induced acute tubulointerstitial nephritis is tubulointerstitial fibrosis if left untreated. The aim of the study was to examine the effect of an outer membrane protein (OMP) of Leptospira santarosai serovar Shermani on extracellular matrix (ECM) accumulation in proximal tubular cells, HK-2 cells. The addition of Leptospira santarosai serovar Shermani OMP for 72 h led to an increase of type I and type IV collagens, measured by real-time PCR and Western blot analysis in a dose-response manner. After addition of Leptospira santarosai serovar Shermani OMP, active TGF-beta1 secretion was increased by nearly two-fold. The addition of anti-TGF-beta1-neutralizing antibodies attenuated the Leptospira santarosai serovar Shermani OMP-induced type I and type IV collagen production, implicating TGF-beta1 in this process. Overexpression of the dominant negative Smad3 prevented the Leptospira santarosai serovar Shermani OMP-induced increase of type I or type IV collagen production. In conclusion, this study clearly demonstrated the stimulatory effect of Leptospira santarosai serovar Shermani OMP on ECM production by enhancing ECM synthesis, which was mediated by a TGF-beta1/Smad-dependent pathway.
Tian
Ya-Chung
YC
Kidney Institute, Department of Nephrology, Chang Gung Memorial Hospital, 199 Tun-Hwa North Road, Taipei 105, Taiwan.
Chen
Yung-Chang
YC
Hung
Cheng-Chieh
CC
Chang
Chiz-Tzung
CT
Wu
Mai-Szu
MS
Phillips
Aled O
AO
Yang
Chih-Wei
CW
D001425:Bacterial Outer Membrane Proteins / Q000494:pharmacology*; D015153:Blotting, Western; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D024141:Collagen Type IV / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005109:Extracellular Matrix / Q000378:metabolism* / Q000382:microbiology; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D007919:Leptospira / Q000235:genetics / Q000378:metabolism*; D007922:Leptospirosis / Q000097:blood; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051900:Smad3 Protein / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
D001425:Bacterial Outer Membrane Proteins; D024042:Collagen Type I; D024141:Collagen Type IV; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1