Models of gouty nephropathy: exploring disease mechanisms and identifying potential therapeutic targets

Abstract

Gouty nephropathy (GN) is a metabolic disease with persistently elevated blood uric acid levels. The main manifestations of GN are crystalline kidney stones, chronic interstitial nephritis, and renal fibrosis. Understanding the mechanism of the occurrence and development of GN is crucial to the development of new drugs for prevention and treatment of GN. Currently, most studies exploring the pathogenesis of GN are primarily based on animal and cell models. Numerous studies have shown that inflammation, oxidative stress, and programmed cell death mediated by uric acid and sodium urate are involved in the pathogenesis of GN. In this article, we first review the mechanisms underlying the abnormal intrinsic immune activation and programmed cell death in GN and then describe the characteristics and methods used to develop animal and cell models of GN caused by elevated uric acid and deposited sodium urate crystals. Finally, we propose potential animal models for GN caused by abnormally high uric acid levels, thereby provide a reference for further investigating the methods and mechanisms of GN and developing better prevention and treatment strategies.

Keywords: animal models; cell model; gouty nephropathy; pathogenesis; uric acid.

FIGURE 1

The role of the intrinsic immune system in the pathogenesis of GN. MSU activates the NF-κB signaling pathway by binding CD14 to Toll-like receptors (TLRs) on the cell membrane to recruit bone marrow differentiation response (MyD88), further activation Iκκ, and activated Iκκ cause phosphorylation of IκB to release NF-κB into the nucleus, which regulates the NF-κB signaling pathway, which modulates nuclear transcription and synthesis of interleukin-1β (Pro-IL-1β). Elevated uric acid levels induce oxidative stress and activate the NF-κB signaling pathway, thereby enhancing NF-κB nuclear transcription and activating the NLRP3 inflammasome, leading to the production of caspase-1. This, in turn, promotes the maturation and release of IL-1β, thereby exacerbating the inflammatory response (All figures were created using the BioRender).

FIGURE 2

Gouty nephropathy (GN) cell apoptosis. Tumor necrosis factor receptor (TNFR) and factor-associated apoptosis (Fas) receptors induce apoptosis by binding to their respective ligands and cleaving Pro-Caspase-8 through the death domains TNF-associated death domain (TRADD) and Fas-associated death domain (FADD), producing active caspase-8 and activating caspase-3, triggering apoptosis. MSU causes oxidative stress and impairs mitochondrial function, leading to the release of the pro-apoptotic factor Bcl-2 (B-cell lymphoma-2), activating the P53 transcription factor, promoting caspase-9 and caspase-3, and ultimately triggering apoptosis.

FIGURE 3

Gouty nephropathy (GN) cell autophagy and ferroptosis. Sodium urate prompts lysosomal swelling and rupture, releasing acidic contents into the cytoplasm. This triggers the activation of NLRP3 inflammasome, leading to the production and release of inflammatory cytokines into the extracellular space, causing cellular autophagy. FPN1 (Ferroportin 1), an iron-excretory protein, plays a crucial role in regulating iron transport. Dysfunctional FPN1 can result in the accumulation of intracellular Fe²⁺, leading to the accumulation of ROS and inducing ferroptosis. Sodium urate can induce ferroptosis by inhibiting the nuclear factor erythroid 2 related factor (NRF2) transcription factor and increasing lipid accumulation in cells.

FIGURE 4

Gouty nephropathy (GN) cell pyroptosis. The formation of inflammasome activates Caspase-1, which cleaves the gasdermin D (GSDMD) protein, activating its N-terminal structural domain, GSDMD-N. GSDMD-N then forms pores in the cell membrane, leading to membrane rupture and the release of IL-1β and IL-18 pro-inflammatory cytokines, inducing cellular pyrolysis. Simultaneously, cytoplasmic lipopolysaccharide (LPS) activates Caspase-4/5/11, which cleaves the GSDMD protein, triggering cellular pyroptosis.