Received February 21, 2006
Accepted on July 10, 2006

BASIC SCIENCE: Pathophysiology of Renal Disease and Progression

Leptospiral Outer Membrane Protein Induces Extracellular Matrix Accumulation through a TGF-1/Smad-Dependent Pathway

Ya-Chung Tian ^*, Yung-Chang Chen ^*, Cheng-Chieh Hung ^*, Chiz-Tzung Chang ^*, Mai-Szu Wu ^*, Aled O. Phillips , and Chih-Wei Yang ^*1

*Kidney Institute, Department of Nephrology, Chang Gung Memorial Hospital, Taipei, and Chang Gung University, Tao Yuan, Taiwan; and Institute of Nephrology, Cardiff University, Wales, United Kingdom

¹ To whom correspondence should be addressed. E-mail: cwyang{at}adm.cgmh.org.tw.

	Abstract

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-1 secretion was increased by nearly two-fold. The addition of anti-TGF-1-neutralizing antibodies attenuated the Leptospira santarosai serovar Shermani OMP-induced type I and type IV collagen production, implicating TGF-1 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-1/Smad-dependent pathway.