Fig 2: MRI-1867 and peripheral CB1 receptor blockade effectively restore metabolic and kidney morphological changes in diet-induced obese (DIO) mice in comparison with inducible NOS inhibition or pair feeding. Six-week-old male C57Bl/6J mice were fed with high-fat diet (HFD) for 18 weeks and then treated chronically by oral gavage with either vehicle (Veh; 1% Tween 80, 4% DMSO, and 95% saline), MRI-1867 (3 mg·kg-1), peripherally restricted CB1 receptor antagonist, JD5037 (3 mg·kg-1), and inducible NOS inhibitor, 1400W (10 mg·kg-1). A parallel group of mice, which was pair fed similarly to the MRI-1867 group, was treated with Veh. Treatment was given for 28 consecutive days. MRI-1867 and JD5037 reduced (a) body weight (BW) and (b) food intake. Both drugs reduced (c) body fat mass and increased (d) lean mass. Histologically, MRI-1867 and JD5037 reduced (e, h) HFD-induced glomerular enlargement, increased (f, h) Bowman's space area, and (g, h) mesangial expansion. Scale bar, 20 µm. Data represent the mean ± SEM from 7 to 14 mice per group. * P < .05, significantly different from diet-induced obese animals treated with Veh; # P < .05, significantly different from diet-induced obese mice treated with MRI-1867; one-way ANOVA, followed by a Bonferroni post hoc test

Fig 3: Elevated renal CB1 receptor (CB1R) and inducible NOS (iNOS) protein expression in humans with chronic kidney disease. (a) Elevated protein expression levels of CB1 receptors and iNOS were detected in 25 kidney biopsies from focal segmental glomerulosclerosis (FSGS), diabetic nephropathy (DN), and obesity-related glomerulopathy (ORG) patients. (b, c) CB1 receptors and iNOS are highly expressed in the kidney tubules in DN and ORG. Scale bar, 100 µm in all images except for the right panels in (b), where the scale is 50 µm. Data represent the mean ± SEM from six normal, eight DN, and 10 ORG kidney samples. * P < .05, significantly different from normal kidney; one-way ANOVA, followed by a Bonferroni post hoc test

Fig 4: A greater efficacy of MRI-1867 in restoring kidney function in diet-induced obese mice in comparison with peripheral CB1 receptor blockade, inducible NOS inhibition, or pair feeding. MRI-1867 or JD5037 treatment reduced (a) BUN levels and (b) the kidney-to-body weight ratio. Only MRI-1867 was effective in reducing urinary (c) albumin, (d) creatinine, and (e) the albumin-to-creatinine (ACR) ratio, as well as the urinary secretion levels of (f) kidney injury marker 1 (KIM-1) and (g) tissue inhibitor of metalloproteinase 1 (TIMP-1). Data represent the mean ± SEM from 7 to 14 mice per group. * P < .05, significantly different from diet-induced obese animals treated with Veh; # P < .05, significantly different from diet-induced obese mice treated with MRI-1867; one-way ANOVA, followed by a Bonferroni post hoc test

Fig 5: Graphical illustration of the interaction of CB1 and TRPV1 by cannabinoids. A ACEA activates both TRPV1 and CB1 in a native setting, leading to no observed inhibition. B when TRPV1 is inhibited, activation of CB1 leads to an attenuation of the CGRP release