Kidney-based in vivo model for drug-induced nephrotoxicity testing

Abstract

The need is critical and urgent for a real-time, highly specific, and sensitive acute kidney injury biomarker. This study sought to establish a sensitive and specific Miox-NanoLuc transgenic mouse for early detection of drug-induced nephrotoxicity. We generated Miox-NanoLuc transgenic mice with kidney-specific NanoLuc overexpression. Our data showed that Miox-NanoLuc-produced luminescence was kidney-specific and had good stability at room temperature, 4 °C, − 20 °C, and repeated freeze–thaw cycles. Serum levels of BUN and creatinine were significantly increased at day 2 or 3 in cisplatin-treated mice and at day 5 in aristolochic acid (AAI)-treated mice. Particularly, the serum and urine Miox-NanoLuc luminescence levels were significantly increased at day 1 in cisplatin-treated mice and at day 3 in AAI-treated mice. Renal pathological analysis showed that the kidney sections of cisplatin-treated mice at day 5 and AAI-treated mice at day 13 showed cytolysis and marked vacuolization of tubular cells. In conclusion, we developed a new platform to early quantify drug-induced nephrotoxicity before serum BUN and creatinine levels increased and pathological tubular cell injury occurred. This model may serve as an early detection for drug- and food-induced nephrotoxicity and as an animal model to investigate tubular cell injury.

Nontoxic Metal-Free Visible Light-Responsive Carbon Nitride Quantum Dots Cause Oxidative Stress and Cancer-Specific Membrane Damage

“… Similarly, the levels of blood urea nitrogen (BUN) and creatinine (CRE) were comparable to those of the control groups, suggesting no signs of renal dysfunction (Figure S7B). Elevated levels of BUN and CRE are markers for nephrotoxicity or renal dysfunction …”

“…Elevated levels of BUN and CRE are markers for nephrotoxicity or renal dysfunction. 46 Troponin-I is involved in the regulation of cardiac muscle contraction, and high levels of serum troponin indicate myocardial injury. Qualitative immunoassay demonstrated an absence of troponin-I in the serum of treated mice, implying no signs of cardiac dysfunction (Figure S7E).…”

Cisplatin Mouse Models: Treatment, Toxicity and Translatability

“…Cisplatin mouse models have been used to investigate pharmacokinetics and tissue distribution of cisplatin [15][16][17], the repair capacity of cisplatin-DNA adducts [18], the molecular mechanisms of cisplatin toxicity [19][20][21][22][23] and to test a new generation of platinumbased chemotherapy drugs or adjunctive therapies [24][25][26][27][28][29][30][31][32][33][34][35], or other potential agents or strategies to prevent or treat cisplatin toxicities [36][37][38][39][40][41].…”

Aristolochic acid I induces proximal tubule injury through ROS/HMGB1/mt DNA mediated activation of TLRs

“…31,35 Previous studies investigating the mechanisms of AAN suggested that AAI acts mainly on proximal renal tubular epithelial cells 36,37 activating MAPK/extracellular signal-regulated kinase 1/2 (MEK/ERK1/2) signalling pathway, followed by depletion of intracellular GSH, 38 NQO1, CYP1A1/2, reduced organic anion transporters (OAT), inhibition of PI3K-Akt signalling, and activation of NF-κB, mitophagy, Rap1 signalling and TCA cycle. 31,[37][38][39][40][41][42] Several reports have proposed a role for the organic anion (OA) transporter (OAT) family in AA-mediated nephrotoxicity. 43,44 Recent evidence indicates that AA is concentrated within proximal tubular epithelial cells via the basolateral OAT (OAT1), which exchanges organic anions such as paraaminohippurate (PAH) and AA for α-ketoglutarate.…”