5/6 nephrectomy induces different renal, cardiac and vascular consequences in 129/Sv and C57BL/6JRj mice

Abstract

Experimental models of cardiovascular diseases largely depend on the genetic background. Subtotal 5/6 nephrectomy (5/6 Nx) is the most frequently used model of chronic kidney disease (CKD) in rodents. However, in mice, cardiovascular consequences of 5/6 Nx are rarely reported in details and comparative results between strains are scarce. The present study detailed and compared the outcomes of 5/6 Nx in the 2 main strains of mice used in cardiovascular and kidney research, 129/Sv and C57BL/6JRj. Twelve weeks after 5/6 Nx, CKD was demonstrated by a significant increase in plasma creatinine in both 129/Sv and C57BL/6JRj male mice. Polyuria and kidney histological lesions were more pronounced in 129/Sv than in C57BL/6JRj mice. Increase in albuminuria was significant in 129/Sv but not in C57BL/6JRj mice. Both strains exhibited an increase in systolic blood pressure after 8 weeks associated with decreases in cardiac systolic and diastolic function. Heart weight increased significantly only in 129/Sv mice. Endothelium-dependent mesenteric artery relaxation to acetylcholine was altered after 5/6 Nx in C57BL/6JRj mice. Marked reduction of endothelium-dependent vasodilation to increased intraluminal flow was demonstrated in both strains after 5/6 Nx. Cardiovascular and kidney consequences of 5/6 Nx were more pronounced in 129/Sv than in C57BL/6JRj mice.

Figure 1

Evolution of body weight (A,B) and urine output (C,D) from week 0 (W0; 5/6 Nx) to W12 (sacrifice) in sham-operated and 5/6 Nx C57BL/6JRj (A,C) and 129/Sv (B,D) mice (n = 10 per group). *p < 0.05: sham vs. 5/6 Nx, **p < 0.01: sham vs. 5/6 Nx, ***p < 0.001: vs. 5/6 Nx. Plasma creatinine at week 12 (E) and aldosteronuria (F) in sham-operated and 5/6 Nx C57BL/6JRj and 129/SV mice (n = 8–9 per group). *p < 0.05: sham vs 5/6 Nx, ***p < 0.001: sham vs 5/6 Nx.

Figure 2

Scoring of kidney lesions 12 weeks after surgery in sham-operated and 5/6 Nx C57BL/6JRj and 129/Sv mice (n = 6–10 per group). (A) Glomerular sclerosis (GS) lesions, (B) Tubular damage (TD) lesions, (C) Interstitial fibrosis (IF) lesions, (D) Interstitial inflammation (II) lesions, (E) Vascular thickening (VT) lesions, (F) Vascular fibrosis (VF) lesions. ***p < 0.001: sham vs 5/6 Nx, ^$p < 0.05: 5/6 Nx (129/Sv) vs. 5/6 Nx (C57BL/6JRj), ^$$$p < 0.001: 5/6 Nx (129/Sv) vs. 5/6 Nx (C57BL/6JRj).

Figure 3

Evolution of systolic blood pressure from week 0 (W0; 5/6 Nx) to W12 (sacrifice) in sham-operated and 5/6 Nx C57BL/6JRj (A) and 129/SV (B) mice (n = 10 per group). *p < 0.05: sham vs. 5/6 Nx, ***p < 0.001: vs. 5/6 Nx. Heart weight (w) to tibia length ratio (C) and morphometric quantification of left ventricular cardiac fibrosis determined 12 weeks after surgery (D) in sham-operated and 5/6 Nx C57BL/6JRj and 129/SV mice (B) (n = 7–9 per group). **p < 0.01: sham vs. 5/6 Nx, ^$$p < 0.01: 5/6 Nx (129/Sv) vs. 5/6 Nx (C57BL/6JRj), ***p < 0.001: sham vs. 5/6 Nx, ^$$$p < 0.001: 5/6 Nx (129/Sv) vs. 5/6 Nx (C57BL/6JRj).

Figure 4

Relaxing responses of pre-contracted mesenteric arteries in response to acetylcholine (A,B) and sodium nitroprusside (C,D) in sham-operated and 5/6 Nx C57BL/6JRj (A,C) and 129/Sv (B,D) mice (n = 7–8 per group). Dilatory responses of pre-constricted mesenteric arteries in response to stepwise increase in intraluminal flow in sham-operated and 5/6 Nx C57BL/6JRj (E) and 129/Sv (F) mice (n = 7–8 per group). *p < 0.05: sham vs. 5/6 Nx, **p < 0.01: sham vs. 5/6 Nx, ***p < 0.001: sham vs. 5/6 Nx.