Background and Purpose: Obesity, an important risk factor for developing chronic kidney disease (CKD), affects the kidneys by two main molecular signalling pathways: the endocannabinoid/CB 1 receptor system, whose activation in obesity promotes renal inflammation, fibrosis, and injury, and the inducible NOS (iNOS), which generates ROS resulting in oxidative stress. Hence, a compound that inhibits both peripheral CB 1 receptors and iNOS may serve as an effective therapeutic agent against obesity-induced CKD.Experimental Approach: Here, we describe the effect of a novel peripherally restricted, orally bioavailable dual CB 1 receptor/iNOS antagonist, MRI-1867(3 mg·kg −1 ), in ameliorating obesity-induced CKD, and compared its metabolic and renal efficacies to a stand-alone peripheral CB 1 receptor antagonist (JD5037; 3 mg·kg −1 ), iNOS antagonist (1400W; 10 mg·kg −1 ), and pair feeding. Mice with highfat diet-induced obesity were treated orally with these compounds or vehicle (Veh) for 28 days. Standard diet-fed mice treated with Veh served as controls.Key Results: Enhanced expression of CB 1 receptors and iNOS in renal tubules was found in human kidney patients with obesity and other CKDs. The hybrid inhibitor ameliorated obesity-induced kidney morphological and functional changes via decreasing kidney inflammation, fibrosis, oxidative stress, and renal injury. Some of these features were independent of the improved metabolic profile mediated via inhibition of CB 1 receptors. An additional interesting finding is that these beneficial effects on the kidney were partially associated with modulating renal adiponectin signalling.Conclusions and Implications: Collectively, our results highlight the therapeutic relevance of blocking CB 1 receptors and iNOS in ameliorating obesity-induced CKD.---

Activation of the cannabinoid-1 receptor (CB1R) and the mammalian target of rapamycin complex 1 (mTORC1) in the renal proximal tubular cells (RPTCs) contributes to the development of diabetic kidney disease (DKD). However, the CB1R/mTORC1 signaling axis in the kidney has not been described yet. We show here that hyperglycemia-induced endocannabinoid/CB1R stimulation increased mTORC1 activity, enhancing the transcription of the facilitative glucose transporter 2 (GLUT2) and leading to the development of DKD in mice; this effect was ameliorated by specific RPTCs ablation of GLUT2. Conversely, CB1R maintained the normal activity of mTORC1 by preventing the cellular excess of amino acids during normoglycemia. Our findings highlight a novel molecular mechanism by which the activation of mTORC1 in RPTCs is tightly controlled by CB1R, either by enhancing the reabsorption of glucose and inducing kidney dysfunction in diabetes or by preventing amino acid uptake and maintaining normal kidney function in healthy conditions.

Tubulopathy plays a central role in the pathophysiology of diabetic kidney disease (DKD). Under diabetic conditions, the kidney proximal tubule cells (KPTCs) are exposed to an extensive amount of nutrients, most notably glucose; these nutrients deteriorate KPTCs function and promote the development and progression of DKD. Recently, the facilitative glucose transporter 2 (GLUT2) in KPTCs has emerged as a central regulator in the pathogenesis of DKD. This has been demonstrated by identifying its specific role in enhancing glucose reabsorption and glucotoxicity, and by deciphering its effect in regulating the expression of the sodium-glucose transporter 2 (SGLT2) in KPTCs. Moreover, reduction/deletion of KPTC-GLUT2 has been recently found to ameliorate DKD, raising the plausible idea of considering it as a therapeutic target against DKD. However, the underlying molecular mechanisms by which GLUT2 exerts its deleterious effects in KPTCs remain vague. Herein, we review the current findings on the proximal tubule GLUT2 biology and function under physiologic conditions, and its involvement in the pathophysiology of DKD. Furthermore, we shed new light on its cellular regulation during diabetic conditions.

Environmental heat load (HL) adversely affects the performance of dairy cows. The endocannabinoid system (ECS) regulates metabolism and the stress response, thus we hypothesized that HL may affect the ECS of dairy cows. Our objective was to determine the levels of endocannabinoids (eCBs) and gene and protein expressions of the ECS components in adipose tissue (AT) and plasma of early postpartum (PP) and late-lactation cows. In addition, we examined eCBs in milk, and studied the interaction of eCBs with bovine cannabinoids receptors CB1 and CB2. In the first experiment, plasma and AT were sampled from cows calving during summer (S, n = 9) or winter (W, n = 9). Dry matter intake (DMI) and energy balance (EB) were lower in S vs. W, and relative gene expressions of transient-receptor-potential-cation-channel-subfamily-V-member-1 (TRPV1), the cannabinoid receptors CNR1 (CB1) and CNR2 (CB2), and monoglyceride lipase (MGLL) were decreased in AT of S compared to W. Protein abundance of peroxisome proliferator-activated-receptor-alpha (PPAR-α) was decreased, while tumor-necrosis factor-α (TNF-α) was increased in AT of S vs. W. Other components of the ECS were not different between S and W calving cows. To study whether the degree of HL may affect the ECS, we performed a second experiment with 24 late-lactation cows that were either cooled (CL) or not cooled (heat-stressed; HS) during summer. DMI was lower in HS vs. CL, AT protein abundance of PPAR-α was lower, and TRPV1 tended to be lower in HS vs. CL, but other components of the ECS were not different between groups. Milk levels of 2-arachidonoylglycerol (2-AG) tended to increase in HS vs. CL. Additionally, modeling of the bovine cannabinoid receptors demonstrated their binding to anandamide and 2-AG. Environmental HL, possibly via lower intake, is associated with limited alterations in ECS components in AT of dairy cows.

BACKGROUND AND AIMS Diabetic kidney disease (DKD), the renal manifestation of diabetes, contributes to increased morbidity and mortality of patients with diabetes. Activation of the cannabinoid-1 receptor (CB1R) and the mammalian target of rapamycin complex 1 (mTORC1) in the renal proximal tubular cells (RPTCs) contributes to the development of DKD. However, whether these two signalling molecules interact with each other to regulate kidney function during health and disease has not been described yet. METHOD By using a multidisciplinary approach that includes pharmacological and genetic manipulations of CB1R and mTORC1, we assessed the effect of CB1R activation/inhibition on mTORC1 activity under conditions of acute and chronic hyperglycaemia or normoglycaemia in RPTCs and mice. RESULTS We showed hyperglycaemia-induced endocannabinoid/CB1R stimulation. This stimulation increased mTORC1 activity and resulted in enhancing the expression of sterol regulatory element-binding protein 1c (SREBP1c) and its nuclear translocation, which in turn, induced the transcription of the facilitative glucose transporter 2 (GLUT2), thus leading to the development of DKD in mice. This effect was ameliorated by CB1R or mTORC1 nullification specifically in RPTCs. However, in non-diabetic conditions, CB1R maintained normal activation of mTORC1 by preventing the cellular excess of various amino acids via regulating their transporters, megalin, SLC6A19 and SLC7A5. CONCLUSION Our findings highlight two novel molecular mechanisms by which the activation of mTORC1 in RPTCs is tightly controlled by CB1R, either by enhancing the reabsorption of glucose and inducing renal dysfunction in diabetes or by preventing amino acid uptake and maintaining normal kidney function in healthy conditions. Moreover, this work highlights the therapeutic potential of targeting peripheral CB1Rs for the treatment of DKD, and on the other hand, avoiding its use in non-diabetic patients due to their possible effect on enhancing mTORC1 signalling.