β‑CARYOPHYLLENE AMELIORATES EXPERIMENTAL DIABETIC NEPHROPATHY VIA CB2‑DEPENDENT, α‑KLOTHO–MEDIATED ACTIVATION OF THE RENAL Nrf2/Keap1/HO‑1 AXIS

 

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https://storage.unitedwebnetwork.com/files/1099/550eac3b343ba5151b68e3f49c15706e.pdf
β‑CARYOPHYLLENE AMELIORATES EXPERIMENTAL DIABETIC NEPHROPATHY VIA CB2‑DEPENDENT, α‑KLOTHO–MEDIATED ACTIVATION OF THE RENAL Nrf2/Keap1/HO‑1 AXIS

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Bushra
Zia
Bushra Zia 700043004@uaeu.ac.ae United Arab Emirates University Pharmacology and therapeutics Alain, Abu Dhabi United Arab Emirates *
MF Nagoor Meeran nagoormeeran1985@uaeu.ac.ae United Arab Emirates University Pharmacology and therapeutics Alain, Abu Dhabi United Arab Emirates -
Sheikh Azim azim.sheikh@uaeu.ac.ae United Arab Emirates University Pharmacology and therapeutics Alain, Abu Dhabi United Arab Emirates -
Shreesh Ojha shreeshojha@uaeu.ac.ae United Arab Emirates University Pharmacology and therapeutics Alain, Abu Dhabi United Arab Emirates -
 
 
 
 
 
 
 
 
 
 
 

Despite significant advancement in management of diabetes, one of the diabetic complication, diabetic nephropathy (DN) is a therapeutic enigma characterized by progressive kidney damage. β-caryophyllene (BCP), a naturally available dietary cannabinoid recognized as a cannabinoid receptor type 2 (CB2) agonist, has shown to confer protection in in different organs in diabetic conditions. However, the role of BCP in DN is not yet known, therefore the present study evaluated its role in experimental models of DN and underlying mechanisms.



NRK-52E renal tubular epithelial cells were treated with: (1) normal glucose (5.5 mM), (2) high glucose (HG, 45 mM), (3) HG+BCP (25 µM), and (4) HG+BCP+AM630 (10 µM). Cell viability was quantified at 24/48h. Additionally, adult male C57BL/6 mice received STZ (50 mg/kg) with high fat diet (HFD) for 12 weeks to develop DN. BCP was administered orally (50 mg/kg/day) to examine the effects on various parameters including renal function test, oxidative stress markers (maldonalidehyde, glutathione peroxidase, catalase and superoxide mutase) as well as pro-inflammatory cytokines. H&E staining was performed to reconfirm the subcellular and histoarchitectural changes in kidney tissues. The data were analyzed using ANOVA following Duncan's test (SPSS v24.0). AM630, a CB2R antagonist was employed to demonstrate CB2R-dependent mechanisms.

BCP treatment significantly improved kidney function parameters and reduced markers of inflammation and oxidative stress in mice developed DN. Histological findings reveal preservation of renal tissues that strengthen the biochemical parameters of nephroprotective effects. In cell studies, BCP protected against high glucose-induced damage, and the protective effects were abrogated by AM630, that demonstrate a CB2 receptor-dependent mechanism.


These findings demonstrate that BCP exerts protective effects against DN through CB2 receptor activation, reducing both inflammation and oxidative stress. Given the negligible toxicity, use in food and beverages as well as its dietary availability and efficacy following a CB2R agonist activity, BCP could be a potential candidate for its therapeutic benefits in DN with a pharmacological rationale. These findings could be important given the role of diet, dietary supplements, nutraceuticals and phytopharmaceuticals in managing diabetes and its complication. The findings are relevant for UAE, wherein diabetes and complications are on high rise.

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