Adenosine in the normal kidney significantly elevates in response to cellular damage. The renal A3
adenosine receptor (A3AR) is up-regulated under stress, but the
therapeutic effects of A3AR antagonists on
chronic kidney disease are not fully understood. The present study examined the effect of
LJ-1888 [(2R,3R,4S)-2-[2-chloro-6-(3-iodobenzylamino)-9H-
purine-9-yl]-
tetrahydrothiophene-3,4-diol], a newly developed potent, selective, species-independent, and orally active A3AR antagonist, on unilateral
ureteral obstruction (UUO)-induced renal
fibrosis. Pretreatment with
LJ-1888 inhibited UUO-induced
fibronectin and
collagen I up-regulation in a dose-dependent manner. Masson's trichrome staining confirmed that
LJ-1888 treatment effectively reduced UUO-induced interstitial
collagen accumulation. Furthermore, delayed administration of
LJ-1888 showed an equivalent
therapeutic effect on tubulointerstitial
fibrosis to that of
losartan. Small-interfering A3AR transfection effectively inhibited transforming growth factor-β1 (TGF-β1)-induced
fibronectin and
collagen I up-regulation in proximal tubular cells similar to
LJ-1888, confirming that the renoprotective effect of
LJ-1888 resulted from A3AR blockade. UUO- or TGF-β1-induced
c-Jun N-terminal kinase and
extracellular signal-regulated kinase phosphorylation decreased significantly after
LJ-1888 administration. A3AR blockade reduced UUO- or TGF-β1-induced up-regulation of
lysyl oxidase, which induces cross-linking of extracellular matrix, suggesting that
LJ-1888 may also regulate extracellular matrix accumulation via post-translational regulation. In conclusion, the present data demonstrate that the A3AR antagonist,
LJ-1888, blocked the development and attenuated the progression of renal
fibrosis, and they suggest that
LJ-1888 may become a new therapeutic modality for renal interstitial
fibrosis.