Therapy with a Selective Cannabinoid Receptor Type 2 Agonist Limits Albuminuria and Renal Injury in Mice with Type 2 Diabetic Nephropathy

Abstract

Background/Aims: A critical involvement of the endocannabinoid/cannabinoid receptor system in diabetes and its complications has been recognized. Experimental evidence suggested that activation of the cannabinoid receptor type 2 (CB₂), which is expressed in the kidney by podocytes and inflammatory cells, had a protective role in early streptozotocin-induced type 1 diabetes in mice. No experimental evidence is so far available on the effects of CB₂ agonists in type 2 diabetes. In this study, we investigated the effects of a CB₂ agonist given at a phase of overt disease on renal functional and structural changes in BTBR ob/ob mice, a model of type 2 diabetic nephropathy. Methods: BTBR ob/ob mice received, from 10 to 21 weeks of age, vehicle, the selective CB₂ agonist HU910, or lisinopril used as standard therapy for comparison. BTBR wild-type mice served as controls. Results: Treatment with CB₂ agonist reduced progressive albuminuria of BTBR ob/ob mice to a similar extent as ACE inhibitor. The antiproteinuric effect of CB₂ agonist was associated with the amelioration of the defective nephrin expression in podocytes of diabetic mice. CB₂ agonist limited mesangial matrix expansion, fibronectin accumulation and sclerosis. Glomerular infiltration of Mac-2-positive monocytes/machrophages was attenuated by CB₂ agonist, at least in part due to the drug's ability to reduce MCP-1 chemotactic signals. Renoprotective effects of CB₂ were similar to those achieved by ACE inhibitor. Conclusion: These results suggest that CB₂ agonism is a potential option to be added to the available therapeutic armamentarium for type 2 diabetic nephropathy.

Addition of cyclic angiotensin-(1-7) to angiotensin-converting enzyme inhibitor therapy has a positive add-on effect in experimental diabetic nephropathy

“…The time course of systolic blood pressure is shown in Figure 1a. As previously reported, 24,25 systolic blood pressure levels in BTBR ob/ob mice given vehicle were comparable with those measured in WT mice. A decreasing systolic blood pressure effect was recorded in cAng-(1-7)-treated diabetic mice at the end of the study (P < 0.05 vs. vehicle).…”

“…Albuminuria was stabilized by both cAng-(1-7) and lisinopril, and levels were significantly lower than in vehicle-treated mice from 16 weeks onward. Cyclic Ang-(1-7) limits glomerular damage in BTBR ob/ob mice Diabetic BTBR ob/ob mice showed the characteristic histologic lesions consisting of mesangial matrix expansion, mesangiolysis, and glomerulosclerosis 24,25 (Figure 2). Moderate mesangial matrix expansion was found in vehicle-treated mice, which was reduced by cAng-(1-7) (P < 0.01 vs. vehicle) but not lisinopril (P ¼ 0.069 vs. vehicle) ( Figure 2).…”

“…This dose of lisinopril was shown to be renoprotective in BTBR ob/ob mice. 25 Treatment lasted until 19 to 20 weeks of age. BTBR WT mice served as controls (n ¼ 8).…”

“…21,22 The thioether-cyclized Ang-(1-7) combined strongly enhanced proteolytic resistance with improved activity, compared with the linear counterpart. 21,23 In this study we wanted to evaluate the effect of the stable lanthipeptide cAng-(1-7) in comparison with the ACE inhibitor lisinopril on renal disease progression in BTBR ob/ob mice, a model of type 2 diabetic nephropathy, 24,25 beginning treatment at an established phase of the disease. We also investigated whether adding the lanthipeptide cAng-(1-7) to lisinopril is more effective than using the ACE inhibitor alone.…”

MicroRNA-184 is a downstream effector of albuminuria driving renal fibrosis in rats with diabetic nephropathy

“…Fibrosis is at the core of the high morbidity and mortality rates associated with diabetic nephropathy but specific therapeutic options with this target are not yet available in clinics. Studies in animal models of diabetes have contributed to defining intracellular and molecular pathways driving renal fibrosis, which include the activation of the renin–angiotensin system, protein kinase C, TGF-β1 and monocyte chemoattractant protein-1 (MCP-1) and the upregulation of plasminogen activator inhibitor-1 (PAI-1), connective tissue growth factor (CTGF)/CCN2, collagen and cytokines [8–11]. Recent studies link fibrosis to changes in microRNAs (miRNAs), a class of short (21–24 nucleotides) noncoding RNAs that regulate gene expression through post-translational and epigenetic mechanisms and thereby affect several cellular processes, from development to disease conditions [12–14].…”