Development of a Model of Chronic Kidney Disease in the C57BL/6 Mouse with Properties of Progressive Human CKD

Abstract

Chronic kidney disease (CKD) is a major healthcare problem with increasing prevalence in the population. CKD leads to end stage renal disease and increases the risk of cardiovascular disease. As such, it is important to study the mechanisms underlying CKD progression. To this end, an animal model was developed to allow the testing of new treatment strategies or molecular targets for CKD prevention. Many underlying risk factors result in CKD but the disease itself has common features, including renal interstitial fibrosis, tubular epithelial cell loss through apoptosis, glomerular damage, and renal inflammation. Further, CKD shows differences in prevalence between the genders with premenopausal women being relatively resistant to CKD. We sought to develop and characterize an animal model with these common features of human CKD in the C57BL/6 mouse. Mice of this genetic background have been used to produce transgenic strains that are commercially available. Thus, a CKD model in this strain would allow the testing of the effects of numerous genes on the severity or progression of CKD with minimal cost. This paper describes such a mouse model of CKD utilizing angiotensin II and deoxycorticosterone acetate as inducers.

Figure 1

Ang II/DOCA salt model of chronic kidney disease in the C57BL/6 mouse. Graph describing the time course of CKD development.

Figure 2

Development of hypertensive proteinuria in Ang II/DOCA salt model of CKD in the C57BL/6 mouse. For all graphs, ∗ indicates a significant difference between two groups where P < 0.05. For (a)–(d), □ signifies pretreatment, whereas ■ signifies 21-day posttreatment with Ang II/DOCA. (a), (b) Changes in systolic and diastolic blood pressure in response to Ang II/DOCA. (c), (d) Total 24 h urinary protein and albumin excretion with Ang II/DOCA treatment. (e) Time-course development of proteinuria, expressed as total 24-hour protein excretion at days 7, 14, 18, and 21 posttreatment with Ang II/DOCA.

Figure 3

Renal tissue damage in response to Ang II/DOCA salt CKD mouse model. For all graphs, ∗ indicates a significant difference between two groups where P < 0.05. Effect of Ang II/DOCA salt model on (a), (b) protein cast formation in the cortex and medulla, (c), (d) glomerulosclerosis, (e), (f) apoptosis, (g), (h) macrophage (F4/80+ cells) infiltration, and (i) interstitial fibrosis (Masson's trichrome staining).

Figure 4

Effect of Ang II/DOCA salt model on cardiac and lung tissue. (a) Images of heart cross-section cardiac hypertrophy in Ang II/DOCA salt model. (b) Graph showing increase in heart weights (mg/g of body weight) in response to Ang II/DOCA where ∗ indicates a significant difference between two groups (P < 0.05). (c) Lung damage (20x, 40x) in response to Ang II/DOCA compared to SHAM controls.

Figure 5

Impact of gender on CKD induced by Ang II/DOCA salt model. For all graphs, ∗ indicates a significant difference between two groups where P < 0.05. Ang II/DOCA salt is denoted by ■, whereas □ denotes SHAM operated controls. “M” and “F” indicate sections from male and female mouse kidneys, respectively. Influence of gender on the development of (a) proteinuria, (b) albuminuria, (c) protein cast formation, (d) apoptosis, and (e) interstitial fibrosis.