Blood pressure and albuminuria in a female mouse model of systemic lupus erythematosus: impact of long-term high salt consumption

Abstract

Hypertension and kidney involvement are common in patients with autoimmune disease. Sodium intake is linked to hypertension in both human and animal studies. Evidence suggests that dietary salt may be an important environmental factor that promotes autoimmune activity. Therefore, we hypothesized that a long-term high-salt diet would accelerate the progression of autoimmunity, hypertension, and albuminuria during systemic lupus erythematosus (SLE), an autoimmune disease that predominantly affects young women and has a high prevalence of hypertension and renal disease. To test this hypothesis, an established experimental model of SLE (female NZBWF1 mice) that develops hypertension and renal disease was used. SLE mice were fed a high-salt (4% NaCl) or normal (0.4% NaCl) diet for 24 wk beginning at 10 wk of age and ending at 34 wk of age, a time by which female NZBWF1 mice typically have hypertension and exhibit signs of renal disease. Plasma anti-dsDNA autoantibodies were measured as an indicator of active SLE disease, and urinary albumin was monitored longitudinally as a marker of renal disease. Arterial pressure was measured in conscious, freely moving mice at 34 wk of age. Urinary endothelin-1 (ET-1) excretion, renal endothelin A and B receptor protein expression, and renal mRNA expression of NOS1, NOS2, NOX2, MCP-1, TNF-α, serum- and glucocorticoid-regulated kinase 1, and interleukin-2 (IL-2) were assessed to determine the impact on gene products commonly altered by a high-salt diet. SLE mice fed a high-salt diet had increased circulating autoantibodies, but the high-salt diet did not significantly affect albuminuria or arterial pressure. Urinary ET-1 excretion was increased, whereas renal endothelin A receptor and IL-2 expression were decreased in response to a high-salt diet. These data suggest that a chronic high-salt diet may not accelerate cardiovascular and renal consequences commonly associated with SLE.

Keywords: autoimmunity; endothelin; hypertension; interleukin-2; systemic lupus erythematosus.

Fig. 1.

Sodium intake is higher in female systemic lupus erythematosus (SLE) mice fed a high-salt diet. SLE mice fed a 4% NaCl diet consume significantly higher NaCl (*P = 0.003, < 0.0001, 0.0004, < 0.0001, and < 0.0001) compared with SLE mice fed a 0.4% NaCl diet, per 2-tailed, unpaired, t test. n = 13 (4% NaCl) and n = 12 (0.4% NaCl). Error bars represent SE.

Fig. 2.

Anti-dsDNA IgG autoantibodies are increased in female systemic lupus erythematosus (SLE) mice fed a high-salt diet at 34 wk of age. Anti-dsDNA IgG autoantibodies are significantly increased in SLE mice fed a 4% NaCl diet by 34 wk of age compared with those fed a 0.4% NaCl diet; *P = 0.0247, 2-tailed, unpaired t test. n = 11 (4% NaCl) and n = 14 (0.4% NaCl). Error bars represent SE.

Fig. 3.

Blood pressure is unchanged in female systemic lupus erythematosus (SLE) mice fed a high-salt diet at 34 wk of age. No significant differences were seen between SLE mice fed a 4% NaCl diet (n = 8) and those fed a 0.4% NaCl diet (n = 5); P = 0.0819, per 2-tailed, unpaired t test. Error bars represent SE. MAP, mean arterial pressure.

Fig. 4.

Albumin excretion is unchanged in systemic lupus erythematosus (SLE) mice fed a 4% NaCl diet compared with those fed a 0.4% NaCl diet; P = 0.30, per 2-tailed, Mann–Whitney test. n = 13 (0.4% NaCl) and n = 12 (4% NaCl). Error bars represent SE.

Fig. 5.

Renal cortex interleukin-2 (IL-2) mRNA levels are decreased in systemic lupus erythematosus (SLE) mice on a chronic high-salt diet. Renal IL-2 mRNA levels significantly decreased in SLE mice fed a 4% NaCl diet compared with those fed a 0.4% NaCl diet; *P = 0.027, per 2-tailed, unpaired t test. Renal mRNA expression of NOS1, NOS2, NOX2, MCP-1, and TNF-α remained unchanged for SLE mice fed a 4% NaCl diet relative to those fed a 0.4% NaCl diet. n = 4 per group. Error bars represent SE.

Fig. 6.

Endothelin-1 (ET-1) excretion is increased in female systemic lupus erythematosus (SLE) mice fed a 4% NaCl diet at 34 wk of age. SLE mice fed a 4% NaCl diet had a significant increase in ET-1 excretion compared with those fed a 0.4% NaCl diet by 34 wk of age; *P = 0.0002, per 2-tailed, unpaired t test. n = 12 (0.4% NaCl) and n = 9 (4% NaCl). Error bars represent SE.

Fig. 7.

Renal endothelin A (ETA) protein expression is reduced in female systemic lupus erythematosus (SLE) mice on a chronic high-salt diet. Relative expression of renal ETA was significantly decreased in SLE mice fed a 4% NaCl diet compared with those fed a 0.4% NaCl diet; *P = 0.0265, per 2-tailed, unpaired t test. n = 11 (0.4% NaCl) and n = 8 (4% NaCl). No differences were seen in endothelin B relative expression. Error bars represent SE. Representative Western blots.

Fig. 8.

Medullary serum- and glucocorticoid-regulated kinase 1 is not altered in systemic lupus erythematosus (SLE) mice fed a high-salt diet. No significant differences were seen between SLE mice fed a 4% NaCl diet and those fed a 0.4% NaCl diet. n = 11 (0.4% NaCl) and n = 8 (4% NaCl). Error bars represent SE.