Cannabinoid Type 2 Receptor Activation Reduces the Progression of Kidney Fibrosis Using a Mouse Model of Unilateral...

Background: Kidney fibrosis is a hallmark consequence of all forms of chronic kidney disease with few available treatment modalities. Material and Methods: In this study, we performed the unilateral ureteral obstruction (UUO) procedure to investigate the effects of a selective cannabinoid type 2 (CB2) agonist receptor, SMM-295, as a nephroprotective therapy. Results: SMM-295 was demonstrated to exhibit 50-fold selectivity over the cannabinoid type 1 (CB1) receptor with an EC₅₀ ∼2 nM. Four other off-targets were identified in the safety panel, but only at the highest concentration (5 mM) tested in the assay demonstrating the relative selectivity and safety of our compound. Administration of SMM-295 (12 mg/kg IP daily) in UUO mice led to a significant decrease of 33% in tubular damage compared to the vehicle-treated UUO mice after 7 days. Consistent with these findings, there was a significant decrease in α-smooth muscle actin and fibronectin, which are markers of tubulointerstitial fibrosis, as determined by Western blot analysis. DNA damage as detected by a classic marker, γ-H2AX, was significantly reduced by 50% in the SMM-295 treatment group compared to vehicle treatment. Genetic knockout of CB2 or administration of a CB2 inverse agonist did not exhibit any beneficial effect on tubulointerstitial fibrosis or kidney tubule injury. Conclusions: In conclusion, our study provides new evidence that SMM-295 can therapeutically target the CB2 receptor with few, if any, physiological off-target sites to reduce kidney tissue damage and slow the fibrotic progression in a mouse model of kidney fibrosis.