Mycophenolate mofetil prevents high-fat diet-induced hypertension and renal glomerular injury in Dahl SS rats

Abstract

We designed experiments to test the hypothesis that Dahl salt-sensitive (SS) rats are sensitive to high-fat diet (HFD)-induced hypertension and renal injury via an inflammatory mechanism. Twelve-week-old Dahl SS rats were maintained on a normal diet (ND; 14% fat), HFD (59% fat), or HFD supplemented with the lymphocyte immunosuppressive agent, mycophenolate mofetil (HFD + MMF; 30 mg/kg/day orally in diet), for a period of 4 weeks. Mean arterial pressure (MAP), metabolic parameters, T lymphocyte (CD3(+)) localization, and renal structural damage were assessed during the studies. Four weeks of HFD significantly elevated MAP and visceral adiposity without changing circulating levels of lipids or adipokines. Immunohistochemical analysis demonstrated that SS rats on HFD had significantly greater numbers of CD3(+) cells in renal glomerular and medullary areas compared to ND SS rats. Additionally, HFD led to increased glomerular injury, but did not alter renal medullary injury. Chronic MMF treatment in HFD-fed Dahl SS rats reduced MAP, visceral adiposity, infiltration of CD3(+) cells in the glomerulus, as well as glomerular injury. However, MMF treatment did not alter HFD-induced infiltration of CD3(+) cells in the renal medulla. In conclusion, Dahl SS rats are sensitized to HFD-induced hypertension and renal glomerular injury via infiltration of T lymphocytes.

Keywords: Dahl salt-sensitive rat; SS-13BN rat; T lymphocytes; glomerulus; high-fat diet; hypertension.

Figure 1

Tracings of 24 h mean arterial blood pressure (MAP) in SS-13^BN rats (A, N = 4–6) and SS rats (B, N = 4–5) on normal diet (ND) or a 4-week high-fat diet (HFD) started at 12 weeks old. A subset of SS rats (N = 5) was treated with MMF (30 mg/kg/day, orally in diet) for the duration of HFD. (C) MAP for 24 h in SS rats in the 3 diet groups at 16 weeks old. *P < 0.05 versus ND, ^†P < 0.05 versus HFD.

Figure 2

Representative glomerular (A–C, quantified in J) and renal cortical blood vessel-related (D–F, quantified in K) and blood vessel-unrelated (G–I, quantified in L) CD3⁺ cells in SS rats on normal diet (ND) (N = 5), high-fat diet (HFD) (N = 5), and HFD treated with (+) MMF (N = 5). *P < 0.05 versus ND, ^†P < 0.05 versus HFD. Triangles highlight CD3⁺ cells and the bar represents 100 μm.

Figure 3

Representative renal medullary blood vessel-related (A–C, quantified in G) and blood vessel-unrelated (D–F, quantified in H) CD3⁺ cells in SS rats normal diet (ND) (N = 5), high-fat diet (HFD) (N = 5), and HFD treated with (+) MMF (N = 5). *P < 0.05 versus ND. Triangles highlight CD3⁺ cells and the bar represents 100 μm.

Figure 4

Representative glomeruli from SS rats on (A) normal diet (ND, 43% glomerular injury) (N = 5), (B) high-fat diet (HFD, 70% injury) (N = 5), and (C) HFD treated with (+) MMF (30% injury) (N = 5). *P < 0.05 versus ND, ^†P < 0.05 versus HFD. Bar represents 50 μm.

Figure 5

Representative renal medullary protein casts from SS rats on (A) normal diet (ND) (N = 5), (B) high-fat diet (HFD) (N = 5), and (C) HFD treated with (+) MMF (N = 5). Bar represents 100 μm.