Modeling Principle

The SD rat acute renal failure (ARF) model is a SCI gold-standard standardized animal model based on single-dose cisplatin toxic intervention, which accurately simulates the progression of clinical drug-induced acute kidney injury to acute renal failure. It focuses on the core pathological mechanisms of drug nephrotoxicity, oxidative stress outbreak, renal inflammatory cascade activation, renal tubular epithelial injury and necrosis, and sharp decline of renal function, and highly recapitulates the complete pathological process of acute renal failure induced by clinical chemotherapeutic drugs and exogenous toxic substances. As a broad-spectrum clinical chemotherapeutic drug, cisplatin has definite dose-dependent targeted renal toxicity. After absorption, it is mainly accumulated in the renal cortex and renal tubular epithelial cells. When exceeding the metabolic and detoxification threshold of the kidney, it directly damages the mitochondrial structure and function of renal tubular epithelial cells, induces massive reactive oxygen species (ROS) outbreak, depletes the renal antioxidant system such as SOD and GSH-Px, causes massive accumulation of MDA lipid peroxidation products, and completely breaks renal redox homeostasis. Meanwhile, cisplatin toxicity significantly activates the classic NF-κB inflammatory pathway, releases a large number of pro-inflammatory factors such as TNF-α, IL-6 and IL-1β, and induces diffuse inflammatory infiltration, interstitial edema and microcirculation disturbance in renal tissues. Sustained oxidative and inflammatory injury further induces apoptosis, shedding, vacuolar degeneration and coagulative necrosis of renal tubular epithelial cells, resulting in rupture of tubular structure and collapse of reabsorption and filtration functions, and ultimately leads to sharp elevation of serum creatinine and blood urea nitrogen, forming typical acute renal failure phenotypes including rapid decline of renal function, tubular necrosis and renal tissue edematous inflammatory injury. SD rats have stable renal tissue structure, highly sensitive response to cisplatin nephrotoxicity, high modeling phenotype uniformity and extremely low individual differences. It is an internationally recognized gold-standard model for researching acute kidney injury pathogenesis, nephrotoxicity mechanism analysis, renal oxidative inflammatory injury intervention and renal protective new drug screening, and is widely applicable to basic mechanism research and preclinical pharmacodynamic evaluation of renal protective drugs.

Modeling Success Criteria

General Status and Renal Macroscopic Phenotypes

Rats in the blank control group were mentally active with normal diet and water intake, and the kidneys were ruddy in color, uniform in texture, smooth in surface without swelling and congestion. Rats in the model group showed listlessness, decreased activity, reduced diet and water intake, slow or even negative weight growth after administration. Bilateral kidneys were swollen in volume, pale and dull in color, turbid and edematous on the surface and hard in texture with significantly increased renal coefficients. The macroscopic edematous injury phenotype was significantly different from that of the blank group, confirming the preliminary formation of the acute renal injury model.

Core Renal Function Biochemical Indexes

The levels of serum creatinine (Scr) and blood urea nitrogen (BUN) in the model group were extremely significantly increased compared with the blank control group, indicating sharp impairment of renal filtration and excretion functions and severe decline of renal function, which accurately conforms to the core biochemical diagnostic criteria of clinical acute renal failure and serves as the most core quantitative gold standard index for successful modeling.

Renal Histopathological Characteristics

HE staining of renal tissues showed typical pathological injuries of acute renal failure: extensive dilation of renal cortical tubules, irregular enlargement of tubular lumen, obvious vacuolar degeneration, granular degeneration, apoptotic shedding and coagulative necrosis of renal tubular epithelial cells; significant renal interstitial edema, widened gaps and diffuse infiltration of a large number of inflammatory cells; the glomerular structure was basically intact without obvious necrosis and damage, which accurately corresponds to the pathological characteristics of clinical drug-induced acute tubular necrotic renal failure with stable and highly specific modeling phenotypes.

Core Oxidative Stress and Inflammatory Indexes

The contents of oxidative damage products ROS and MDA in renal tissues of the model group were significantly upregulated, while the activities of antioxidant enzymes SOD and GSH-Px were significantly decreased, resulting in severe renal oxidative stress imbalance and intense lipid peroxidation damage. Core pro-inflammatory factors (TNF-α, IL-6, IL-1β) were significantly highly expressed, the NF-κB inflammatory pathway was excessively activated, and persistent inflammatory infiltration in renal tissues was obvious, which fully conforms to the core mechanism of oxidative-inflammatory interactive injury mediated by cisplatin nephrotoxicity and serves as the core academic basis for successful model construction.

Model Advantages

As a SCI-certified exclusive gold-standard model for cisplatin-induced acute renal failure, it features a single and pure modeling mechanism and highly targeted renal toxicity, which specifically simulates clinical chemotherapeutic drug-induced acute tubular necrosis and renal failure without glomerular injury interference, and the pathological phenotype is highly consistent with clinical manifestations. It has extremely simple operation, successful modeling with single injection, short cycle (72-hour molding), low cost and extremely low animal mortality. The injury phenotype is stable with high intra-group uniformity and excellent data reproducibility without spontaneous repair deviation. It accurately focuses on the three core pathogenic mechanisms of oxidative stress outbreak, excessive inflammatory activation and renal tubular epithelial necrosis, and is perfectly suitable for preclinical pharmacodynamic and mechanism verification of renal protective, anti-oxidative, anti-inflammatory and renal tubular apoptosis-inhibiting drugs. With clear project mechanism, strong innovation, short experimental cycle and highly recognized industry data, it is fully applicable for project declaration, master and doctoral theses, high-score SCI publication and renal pharmacological transformation research.

Research Applications

The SD rat acute renal failure model is corely applied to the research of drug-induced renal toxicity injury mechanism, renal oxidative stress imbalance mechanism and renal tubular inflammatory apoptosis injury mechanism. It is specially used for screening and evaluating traditional Chinese medicine compounds, natural active ingredients, small chemical molecules and renal protective preparations with effects of renal protection and detoxification, acute renal function injury improvement, anti-oxidation and anti-inflammation, renal tubular necrosis inhibition and renal interstitial edema reduction. It is widely used in the elucidation of acute kidney injury pathogenesis, renal protection target exploration, and preclinical pharmacodynamic verification and mechanism exploration of new anti-renal injury drugs, serving as an essential core standardized model in the fields of renal pharmacology, toxicology and acute kidney injury intervention.

renal oxidative stress injury，cisplatin-induced acute kidney injury，acute renal failure rat model，renal tubular necrosis，preclinical renal protection drug evaluation