A new low-nephron CKD model with hypertension, progressive decline of renal function, and enhanced inflammation in C57BL/6 mice

Abstract

Chronic kidney disease (CKD) is a major health issue in the US. The typical five-sixths nephrectomy (typical 5/6 NX) is a widely used experimental CKD model. However, the typical 5/6 NX model is hypertensive in rats but strain dependent in mice. In particular, C57BL/6 mice with the typical 5/6 NX exhibits normal blood pressure and well-preserved renal function. The goal of the present study was to create a new hypertensive CKD model in C57BL/6 mice. We first characterized the vascular architecture originated from each renal artery branch by confocal laser-scanning microscopy with fluorescent lectin. Then, a novel 5/6 NX-BL model was generated by uninephrectomy combined with 2/3 renal infarction via a ligation of upper renal artery branch on the contralateral kidney. Compared with 5/6 NX-C, the 5/6 NX-BL model exhibited elevated mean arterial pressure (137.6 ± 13.9 vs. 104.7 ± 8.2 mmHg), decreased glomerular filtration rate (82.9 ± 19.2 vs. 125.0 ± 13.9 µl/min) with a reciprocal increase in plasma creatinine (0.31 ± 0.03 vs. 0.19 ± 0.04 mg/dl), and significant renal injury as assessed by proteinuria, histology with light, and transmission electron microscopy. In addition, inflammatory status, as indicated by the level of proinflammatory cytokine TNFα and the leukocyte counts, was significantly upregulated in 5/6 NX-BL compared with the 5/6 NX-C. In summary, we developed a new hypertensive CKD model in C57BL/6 mice with 5/6 renal mass reduction by uninephrectomy and upper renal artery branch ligation on the contralateral kidney. This 5/6 NX-BL model exhibits an infarction zone-dependent hypertension and progressive deterioration of the renal function accompanied by enhanced inflammatory response.