Diabetic nephropathy (DN) constitutes one of the gravest microvascular complications of diabetes mellitus (DM) and stands as a significant contributor to end-stage renal disease (ESRD) [1]. The predominant histological features of DN comprise proteinuria, thickening of the glomerular basement membrane, and enlargement of the mesangial matrix, which may occur with or without nodular sclerosis [2]. As the disease advances, patients experience interstitial fibrosis accompanied by tubular atrophy and arteriolar hyalinosis. This can even lead to podocyte loss, endothelial disruption, and ultimately, nephron loss [3,4]. Currently, the primary approaches for DN patients to retard the progression of renal injury entail controlling blood pressure, lipids, and blood glucose levels [5,6]. Nevertheless, these interventions yield limited efficacy, thereby necessitating the identification of drugs capable of countering DN-associated kidney damage.

Quercetin (3, 3′, 4′, 5, 7-pentahydroxyflavone), a naturally occurring flavonoid polyphenol abundantly present in vegetables and fruits, is renowned for its stability and possesses a broad spectrum of medicinal properties such as anti-allergy, anti-inflammation, antioxidation, and anti-apoptosis [7]. Evidence has shown that quercetin displays a protective effect against ferroptosis in acute kidney injury [8] and diabetic kidney disease (DKD), as evidenced by the activation of the Nrf2/HO-1 signaling pathway [9]. Additionally, Xu et al. [10] reported that quercetin counteracts glucose fluctuation (GF)-induced renal injury in mouse glomerular mesangial cells (MCs) by suppressing aerobic glycolysis via the HIF-1α/miR-210/ISCU/FeS pathway. Recent studies suggest that quercetin has a beneficial impact on DN. For instance, quercetin inhibits the proliferation, inflammation, and oxidative stress of human mesangial cells (HMCs) induced by high glucose (HG) through the miR-485-5p/YAP1 axis [11]. The research by Liu et al. [12] reveals that quercetin reduces podocyte apoptosis by inhibiting the EGFR signaling pathway. Moreover, quercetin can prevent DN by inhibiting tubular epithelial cell apoptosis through the PI3K/AKT pathway [13]. Nevertheless, despite these findings, the molecular mechanisms by which quercetin acts against DN remain largely elusive and require further investigation.

It is currently well established that inflammatory responses and the immune system hold crucial significance in the progression of DN [14]. Macrophages, renowned for their pluripotency and plasticity, have the ability to differentiate into classically activated (M1) cells and alternatively activated (M2) cells, which play opposing roles in inflammation regulation [15]. The dynamic equilibrium of the M1/M2 ratio constitutes a key factor in the mechanisms of DN, which is supported by the observation that there is a significant increase in the number of M1 macrophages and a significant decrease in the number of M2 macrophages [16]. Particularly noteworthy is the innate immune molecule, NOD-like receptor family caspase recruitment domain family domain containing 5 (NLRC5), which is a highly conserved member of the newly discovered NLR-like receptor family [17]. As the largest NLR, NLRC5 has been found to be essential in antigen presentation, inflammation, and tissue fibrosis [18]. In the context of kidney diseases, knockdown of NLRC5 has been shown to attenuate renal I/R injury in vitro through the activation of the PI3K/Akt signaling pathway [19]. Additionally, Li et al. [20] have shown that NLRC5 deficiency protects against acute kidney injury in mice by mediating carcinoembryonic antigen-related cell adhesion molecule 1 signaling. Moreover, Luan et al. [21] have reported that NLRC5 promotes inflammation and fibrosis during DN progression by influencing the NF-κB and TGF-β/Smad pathways. Specifically, Yin et al. [22] recently demonstrated that the NLRC5/NLRP3 pathway plays a significant role in neferine improving hyperuricemic nephropathy by inhibiting M1-type macrophage polarization. Based on these findings, we hypothesize that quercetin may have the potential to improve DN by influencing macrophage polarization regulated by the NLRC5/NLRP3 pathway.

To validate our hypothesis, we carried out in vitro experiments on the mouse RAW 264.7 cell line to investigate the mechanism by which quercetin intervenes in HG-induced macrophage injury. Simultaneously, we induced renal injury in diabetic kidney disease mice using streptozotocin (STZ) to explore the effects of quercetin in the progression of DN. The outcomes of this study are anticipated to bring to light novel information regarding therapeutic targets for DN.