Harmaline improves diabetes-associated renal alterations in nicotinamide/streptozotocin-induced diabetic mice: Possible involvement of oxidative stress, inflammation, and renin–angiotensin system signaling

Abstract

Objective(s): Diabetic nephropathy (DN) is marked by structural and functional kidney damage, driven by oxidative stress, inflammation, and renin–angiotensin system (RAS) dysregulation. Harmaline (HAR), a β-carboline alkaloid with potent antioxidant and anti-inflammatory properties, is a promising multi-target therapeutic candidate. Materials and Methods: Twenty-four male mice were randomized into vehicle control (CO), diabetic (DI; nicotinamide 120 mg/kg+streptozotocin 65 mg/kg), diabetic treated with HAR (DI/HAR; 30 mg/kg), or diabetic treated with metformin (DI/MET; 150 mg/kg). After ten days, renal tissues and blood were analyzed for oxidative stress, inflammatory and RAS markers, microRNA expression, and histopathological alterations. Results: Harmaline reversed the changes in total oxidant status and malondialdehyde levels in kidney tissue of diabetic mice. Histopathological analysis showed significant improvement in kidney injury in diabetic mice receiving harmaline. Harmaline treatment decreased the expression of miR-125b, nuclear factor kappa B (NF-κB), tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6). Also, in the antioxidant pathway, there was an increase in the levels of miR-200a, nuclear factor erythroid-related2 (Nrf2), and NAD(P)H quinone dehydrogenase 1 (Nqo1), and a decrease in ECH-like chelate-associated protein1 (Keap1) in kidney tissue. This treatment also decreased the expression of angiotensin-converting enzyme 1 (ACE1) and angiotensin II receptor 1 (AT1R), as well as angiotensin II levels. Conclusion: Harmaline confers renoprotection in experimental DN by simultaneously regulating oxidative stress, inflammatory signaling, and RAS pathways, supporting its potential as a multi-target therapeutic strategy. This study highlights HAR as a promising candidate for translational intervention in diabetic kidney disease.