The
endocannabinoid system is important in the pathogenesis of
obesity-related metabolic disorders. However, the effect of inhibiting the
endocannabinoid system in type 2
diabetic nephropathy is unclear. Therefore, we examined the effect of the
cannabinoid (CB)1 receptor antagonist,
SR141716, on
insulin resistance and
diabetic nephropathy in db/db mice. Six-week-old db/db mice were treated with the CB1-specific antagonist
SR141716 (10 mg/kg · d) for 3 months. Treatment with
SR141716 significantly improved
insulin resistance and
lipid abnormalities. Concomitantly, CB1 antagonism improved cardiac functional and morphological abnormality, hepatic steatosis, and phenotypic changes of adipocytes into small differentiated forms, associated with increased
adiponectin expression and decreased
lipid hydroperoxide levels.
CB1 receptor was overexpressed in diabetic kidneys, especially in podocytes. Treatment with the
SR141716 markedly decreased urinary
albumin excretion and mesangial expansion and suppressed profibrotic and proinflammatory
cytokine synthesis. Furthermore,
SR141716 improved renal lipid metabolism and decreased urinary
8-isoprostane levels, renal
lipid hydroperoxide content, and renal
lipid content. In cultured podocytes, high-
glucose stimulation increased
CB1 receptor expression, and
SR141716 treatment abolished high-
glucose-induced up-regulation of
collagen and
plasminogen activator inhibitor-1 synthesis. Additionally, knockdown of
CB1 receptor expression by stealth
small interfering RNA abolished high-
glucose-induced
sterol-regulatory
element-binding protein-1 expression in podocytes. These findings suggest that CB1 blockade improves
insulin resistance and protect against renal injury through both metabolic and antifibrotic effects in type 2
diabetic nephropathy. Targeting CB1 blockade could therefore provide a new therapeutic target to prevent type 2
diabetic nephropathy.