T lymphocytes mediate hypertension and kidney damage in Dahl salt-sensitive rats

Abstract

This study examined mechanisms by which immune cells participate in the development of hypertension and renal disease in Dahl salt-sensitive (SS) rats. Increasing dietary salt from 0.4% to 4.0% NaCl significantly increased renal infiltration of T lymphocytes from 8.8 +/- 1.2 x 10(5) to 14.4 +/- 2.0 x 10(5) cells/2 kidneys, increased arterial blood pressure from 131 +/- 2 to 165 +/- 6 mmHg, increased albumin excretion rate from 17 +/- 3 to 129 +/- 20 mg/day, and resulted in renal glomerular and tubular damage. Furthermore, renal tissue ANG II was not suppressed in the kidneys of SS rats fed 4.0% NaCl. Administration of the immunosuppressive agent mycophenolate mofetil (MMF; 20 mg.kg(-1).day(-1)) prevented the infiltration of T lymphocytes and attenuated Dahl SS hypertension and renal disease. In contrast to vehicle-treated rats, Dahl SS rats administered MMF demonstrated a suppression of renal tissue ANG II from 163 +/- 26 to 88 +/- 9 pg/g of tissue when fed high salt. Finally, it was demonstrated that the T lymphocytes isolated from the kidney possess renin and angiotensin-converting enzyme activity. These data indicate that infiltrating T cells are capable of participating in the production of ANG II and are associated with increased intrarenal ANG II, hypertension, and renal disease. The suppression of T-cell infiltration decreased intrarenal ANG II and prevented Dahl SS hypertension and kidney damage. As such, infiltrating cells are capable of participating in the established phase of Dahl SS hypertension.

Fig. 1.

Changes in mean arterial pressure (top) and albumin excretion rate (bottom) in Dahl salt-sensitive (SS) rats fed AIN-76A diet containing 0.4% NaCl followed by 20 days of 4.0% NaCl chow. *P < 0.05 vs. values obtained on 0.4% NaCl chow.

Fig. 2.

Light microscopy of Trichrome-stained sections of renal cortex (A and C, ×40 original magnification) and renal outer medulla (B and D, ×10 magnification) of Dahl SS rats fed 0.4% NaCl (A and B) or 4.0% NaCl chow for 3 wk (C and D). The lower panels depict the calculated glomerular injury score (E), and the percentage of renal outer medulla consisting of protein casts (F) in kidneys of rats fed the 0.4% or 4.0% NaCl diets. *P < 0.05 vs. 0.4% NaCl.

Fig. 3.

Identification of cytotoxic (CD8⁺) and helper (CD4⁺) T lymphocytes in mononuclear cells infiltrating the kidneys of Dahl SS rats (A), absolute number of T-lymphocytes isolated from the kidneys of Dahl SS rats maintained on the 0.4% or 4.0% NaCl chow (B), and immunohistochemical localization of T cells in the kidney of Dahl SS rats fed 4.0% NaCl chow (C, D, ×40 original magnification). T cells were localized in the renal tissue with antibodies directed against the cell surface markers CD3. *P < 0.05 vs. 0.4% NaCl.

Fig. 4.

Mean arterial pressure (top) and urinary albumin excretion rate (bottom) in Dahl SS rats maintained on a 4.0% NaCl diet and administered vehicle or mycophenolate mofetil (MMF; 20 mg·kg⁻¹·day⁻¹ ip) for 3 wk prior to these measurements (n = 5/group). *P < 0.05 vs. vehicle-treated rats on the same diet.

Fig. 5.

Number of infiltrating T lymphocytes in the kidney (top) and renal concentration of ANG II (bottom) in vehicle-treated and MMF-treated Dahl SS rats fed 0.4% or 4.0% NaCl. *P < 0.05 vs. vehicle-treated rats on the same diet.

Fig. 6.

Calculated total renin tissue activity and angiotensin-converting enzyme activity contributed by infiltrating T cells in kidneys of rats fed 0.4% and 4.0% NaCl.