Diabetic kidney disease (DKD) is the leading cause of
end-stage kidney disease, and the current pharmacological treatment for DKD is limited to renin-angiotensin system (RAS) inhibitors.
Adenosine is detectable in the kidney and is significantly elevated in response to cellular damage. While all 4 known subtypes of
adenosine receptors, namely, A1AR, A2aAR, A2bAR, and A3AR, are expressed in the kidney, our previous study has demonstrated that a novel, orally active, species-independent, and selective A3AR antagonist,
LJ-1888, ameliorates unilateral
ureteral obstruction-induced tubulointerstitial
fibrosis. The present study examined the protective effects of
LJ-2698, which has higher affinity and selectivity for A3AR than
LJ-1888, on DKD. In experiment I, dose-dependent effects of
LJ-2698 were examined by orally administering 1.5, 5, or 10 mg/kg for 12 weeks to 8-week-old db/db mice. In experiment II, the effects of
LJ-2698 (10 mg/kg) were compared to those of
losartan (1.5 mg/kg), which is a standard treatment for patients with DKD.
LJ-2698 effectively prevented kidney
injuries such as
albuminuria, glomerular
hypertrophy, tubular injury, podocyte injury,
fibrosis,
inflammation, and oxidative stress in diabetic mice as much as
losartan. In addition, inhibition of
lipid accumulation along with increases in PGC1α, a master regulator of mitochondrial biogenesis, were demonstrated in diabetic mice treated with either
LJ-2698 or
losartan. These results suggest that
LJ-2698, a selective A3AR antagonist, may become a novel therapeutic agent against DKD.