According to the 10th edition of the International Diabetes Federation (IDF) diabetes atlas, the incidence of Diabetes Mellitus (DM) is increasing annually. Furthermore, the global prevalence of the disease currently stands at > 530 million individuals, a figure expected to reach >700 million by 2040, underscoring the disease's troubling trend, especially among younger demographics (Cho et al., 2018; Navaneethan et al., 2023; Saeedi et al., 2019). According to reports, DM or pre-diabetes affects >50 % of the global population, with Type 2 DM (T2DM) accounting for ⁓90 % of reported cases (Ricciardi and Gnudi, 2021; Zheng et al., 2018). Meanwhile, Diabetic Kidney Disease (DKD), a prevalent microvascular consequence in T2DM patients, has been reported in 20 %–40 % of affected individuals (Luk et al., 2017; Wang et al., 2021). Compared to those with DM and without nephropathy, DKD patients have an ⁓30 times higher all-cause mortality rate, a phenomenon attributable to the latter's heightened risk of cardiovascular events, especially before reaching End-Stage Renal Disease (ESRD) (Sagoo and Gnudi, 2020). The high prevalence of DKD further imposes a huge resource strain on healthcare systems.

Notably, DKD could be categorized into two phenotypes: Typical albuminuric phenotype (marked by glomerular lesions) and the non-proteinuric phenotype (characterised by atypical vascular lesions and tubulointerstitial fibrosis) (Wang and Zhang, 2024). This classification implies that the pathogenesis of DKD is multifaceted, encompassing genetic predispositions, Reactive Oxygen Species (ROS), dysregulated glucose metabolism, hemodynamic abnormalities, inflammatory responses, and cellular apoptosis, among other factors (Jiang et al., 2019). Nonetheless, current DKD treatments focus primarily on managing glucose, blood pressure, and inflammation. Despite their effectiveness in the early disease stages, these interventions have been linked with certain limitations, including adverse effects, such as Gastrointestinal (GI) discomfort and potential toxicity.

Traditional Chinese Medicine (TCM), which leverages an intricate system to regulate an individual's health holistically, could offer evidence-based, individualized treatments for DKD. Due to their favorable safety and efficacy, TCM compounds have been widely used in therapeutic interventions, highlighting their significant research and clinical value (Liu et al., 2022). Natural product herbs are highly regarded globally and have been extensively utilized as complementary and alternative therapies for DKD. For instance, Potentilla Discolor Bunge (PDB), a natural plant whose origins could be traced to the ‘Materia Medica for Relief of Famines' (China's initial agronomy and botany monograph from the 14th-15th century) (Ji et al., 2022) and widely distributed in northern and temperate climates, has been traditionally used in China to manage DM (Li et al., 2014, Li et al., 2014; Zhang et al., 2010). Notably, 367 compounds were recently identified from this genus, encompassing terpenoids, flavonoids, phenolic acids, and phenylpropanoids, among others. Medicinal derivatives from these botanicals exhibited diverse pharmacological properties, including antioxidative, hypoglycemic, anti-inflammatory, antitumor, cardiovascular protective, neuroprotective, and hepatoprotective effects (Wu et al., 2022, Wu et al., 2022). Moreover, a previous High-Performance Liquid Chromatography (HPLC) analysis revealed that three potential pharmacodynamic constituents in PDB, Quercetin, β-sitosterol, and Kaempferol, had quantitative ratios of 0.030 %, 0.076 %, and 0.025 %, respectively (Li et al., 2024).

In DM patients, PDB could help regulate blood glucose levels while decreasing Insulin Resistance (IR) (Li et al., 2020; Li, Y. et al., 2014). Although PDB extracts have shown great promise in addressing DM, their mechanisms in relation to the pathogenesis of DKD, a T2DM-related complication, remain unclear. Specifically, PDB's active ingredients, targets of action, and therapeutic effects against DKD are yet to be elucidated, necessitating further research.

Herein, we utilized network pharmacology to examine the primary constituents of PDB, creating a ‘component-target-disease’ network for predicting its pharmacological basis and mechanisms in DKD prevention and treatment. The key signaling pathways initially identified through network pharmacology included the AGE/RAGE and Nrf2 pathways. Stable protein alterations, popularly known as Advanced Glycation End Products (AGEs), are often generated when glucose and its byproducts react spontaneously (Rabbani and Thornalley, 2018). The excessive buildup of these products in individuals with DKD could elicit ROS and inflammation, disrupting the glomeruli and tubules (Kumar Pasupulati et al., 2016). Herein, we developed a rat model of DKD that mirrors human T2DM and a model for AGEs-induced Renal Tubular Epithelial Cell (RTEC) injury. Notably, AGEs-accumulation in renal tissues is well-known to cause renal injury in DKD. Using these models, we validated the regulatory interactions between core PDB components and targets both in vivo and in vitro, elucidated the material basis and mechanisms of PDB in preventing and managing DKD, and identified novel TCM targets for DKD prevention and management.