Background: Diabetic nephropathy (DN), a serious diabetic complication, currently has limited treatment options. Yulan Jiangtang capsules (YL) are a clinically approved traditional Chinese medicine formula for glycemic control and diabetes-related complications. Nevertheless, the underlying mechanisms of their therapeutic effects remain incompletely elucidated.
Purpose: This study employed a comprehensive strategy involving network pharmacology, metabolomics, and experimental validation to investigate the potential mechanisms of YL in DN.
Methods: Firstly, initial investigations combined UPLC-MS technology with network pharmacology to systematically identify the key components, core targets, and associated pathways of YL. Secondly, experimental rats were fed a high-fat/high-glucose diet for 4 weeks, followed by diabetes induction using STZ injection (35 mg/kg; success criteria: random glucose ≥16.7 mmol/l at 72 h). 2 weeks later, Diabetic nephropathy rats (confirmed by elevated urinary protein and microalbumin) were randomized into five groups (n = 16/group): Model, Met + Irb (150+15.75 mg/kg), and YL (189, 378, 756 mg/kg). YL and Met+Itb were orally administered for 10 weeks, twice a day. FBG, GHb, and some indicators reflecting renal function were determined. Kidney tissue pathology was evaluated using H&E staining, PAS staining, and TEM. Thirdly, the functional role of the AGEs-RAGE-NF-κB signaling pathway was experimentally validated. Finally, non-targeted urinary metabolomics was performed using UHPLC-QE-MS.
Results: Network pharmacology results showed 119 active compounds identified from YL could effectively treat DN through multiple mechanisms, including blood sugar control, anti-inflammation, anti-oxidation, and angiogenesis. Animal experiments confirmed that YL demonstrated significant anti-diabetic and renoprotective effects in DN rats, notably improving glycemic control and ameliorating kidney damage. Among them, high-dose YL could significantly reduce blood glucose levels (p < 0.05), and improved kidney function by decreasing FBG, GHb, 24-hour urine protein, mALB, SCR, BUN and UACR (p < 0.05 or p < 0.01). It also decreased MDA, IL-1β, IL-6, and TNF-α, elevated SOD, and inhibited the expressions of AGEs, RAGE and NF-κB in the kidney of DN rats (p < 0.05). Additionally, YL treatment could reverse the increase in five metabolites (including 2'-Deoxycytidine, octopine, palmitic acid, N-Carbobenzyloxy-glycine, and N-Acetylneuraminic acid) and the decrease in four metabolites (including α-Linolenic acid, l-Citrulline, l-tyrosine, and N-l-gamma-Glutamyl-l-leucine) in the urine of DN rats. These metabolites are involved in pathways such as phenylalanine/tyrosine/tryptophan biosynthesis, phenylalanine metabolism, α-linolenic acid metabolism, and arginine biosynthesis.
Conclusion: YL treatment significantly mitigates kidney injury in DN rats by modulating the AGEs-RAGE axis and restoring metabolic homeostasis, thereby attenuating oxidative stress and inflammation. This research provides an experimental basis for the clinical application of YL in treating DN.
Keywords: AGEs/RAGE signaling pathway; Diabetic nephropathy; Metabolomics; Network pharmacology; Yulan Jiangtang capsules.
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