Molecular mechanisms of renoprotection and safety profile of Salvia miltiorrhiza (Danshen)

Background Chronic kidney disease (CKD), affecting 10–15% globally, represents a major public health burden exacerbated by diabetes, hypertension, and aging populations. Current treatments (e.g., renin-angiotensin system [RAS] blockers, dialysis, transplantation) have limitations including therapeutic constraints, access inequity and side effects. Salvia miltiorrhiza (Danshen), a traditional Chinese medicine historically used for cardiovascular and renal disorders, demonstrates promising renoprotective properties. Its bioactive constituents (e.g., tanshinones, salvianolic acids) exhibit antioxidant, anti-inflammatory, anti-fibrotic, and cell death-regulating effects in preclinical models. While developed into injectable formulations that have shown clinical efficacy, a systematic analysis of Danshen's molecular mechanisms and a critical evaluation of its application safety are needed to guide rational utilization in CKD management. Methods A comprehensive literature review was conducted using databases such as PubMed, Web of Science, and China National Knowledge Infrastructure (CNKI). Preclinical studies (e.g., animal models of diabetic nephropathy, ischemia-reperfusion injury, and renal fibrosis) and clinical trials involving Danshen formulations were included. Mechanistic analyses focused on oxidative stress, inflammation, autophagy/apoptosis regulation, and fibrosis pathways. Safety assessments encompassed evaluations of toxicity studies, adverse event reports, and dosage thresholds for key components. Results This study systematically elucidates the renoprotective effects of Danshen and its bioactive components. Specific findings are as follows: Antioxidant effect: Salvianolic acid B (SAB) and tanshinone IIA (Tan IIA) activate the nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) pathway, increase superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and reduce malondialdehyde (MDA) by 30%-50% in diabetic nephropathy and ischemia-reperfusion injury models. Anti-inflammatory effect: SAB and Tan IIA suppress nuclear factor kappa-B (NF-κB) and toll-like receptor 4 (TLR4) signaling, decreasing pro-inflammatory cytokines (tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β)) and reducing macrophage infiltration. Regulation of autophagy and apoptosis: Tan IIA modulates the microRNA-34a-5p (miR-34a-5p)/Notch1 axis to promote autophagy and inhibit apoptosis; SAB reduces Bcl-2-associated X protein/B-cell lymphoma 2 (Bax/Bcl-2) ratio and caspase-3 cleavage in renal tubular cells. Anti-fibrotic effect: Tan IIA and salvianolic acid C inhibit transforming growth factor-beta (TGF-β)/Smad signaling, reduce fibronectin and collagen deposition, and reverse epithelial-mesenchymal transition (EMT). Safety profile: High-dose Danshen injection (>9-fold clinical dose) causes vascular endothelial injury. Dose thresholds for safe use were identified (e.g., Tan IIA ≤25 mg/kg in rats; SAB ≤200 mg/kg in mice). Common adverse reactions include rash and gastrointestinal disturbance, while rare anaphylactic shock may occur. Conclusions Danshen and its bioactive constituents exhibit multitarget renal protective effects through antioxidative, anti-inflammatory, and anti-fibrotic mechanisms, but require cautious use due to dose-dependent toxicity. Future research should prioritize pharmacokinetic studies, long-term safety assessments, and randomized controlled trials.