Rag1-null Dahl SS rats reveal that adaptive immune mechanisms exacerbate high protein-induced hypertension and renal injury

Abstract

The present study, performed in Dahl salt-sensitive (SS) and SS- Rag1 rats lacking T and B lymphocytes, tested the hypothesis that immune cells amplify salt-sensitive hypertension and kidney damage in response to a high-protein diet. After being weaned, SS and SS- Rag1 rats were placed on an isocaloric, 0.4% NaCl diet containing normal (18%) or high (30%) protein. At 9 wk of age, rats were switched to a 4.0% NaCl diet containing the same amount of dietary protein and maintained on the high-salt diet for 3 wk. After being fed the high-salt diet, SS rats fed high protein had amplified hypertension and albumin excretion (158.7 ± 2.6 mmHg and 140.8 ± 16.0 mg/day, respectively, means ± SE) compared with SS rats fed normal protein (139.4 ± 3.6 mmHg and 69.4 ± 11.3 mg/day). When compared with the SS rats, SS- Rag1 rats fed high protein were protected from exacerbated hypertension and albuminuria (142.9 ± 5.8 mmHg and 66.2 ± 10.8 mg/day). After 3 wk of the high-salt diet, there was a corresponding increase in total leukocyte infiltration (CD45) in the kidneys of both strains fed high-protein diet. The SS- Rag1 rats fed high-protein diet had 74-86% fewer CD3 T lymphocytes and CD45R B lymphocytes infiltrating the kidney versus SS rats, but there was no difference in the infiltration of CD11b/c monocytes and macrophages, suggesting that the protective effects observed in the SS- Rag1 rats are specific to the reduction of lymphocytes. With the SS- Rag1 rats utilized as a novel tool to explore the effects of lymphocyte deficiency, these results provide evidence that adaptive immune mechanisms contribute to the exacerbation of salt-induced hypertension and renal injury mediated by increased dietary protein intake.

Parental Dietary Protein Source and the Role of CMKLR1 in Determining the Severity of Dahl Salt-Sensitive Hypertension

“…Additionally, nutrition and dietary factors have a tremendous impact on immune function and the host's ability to separate and protect itself from its environment [38][39][40] , and the role of the immune system in the development and amplification of Dahl SS hypertension is wellestablished 41 . Recent studies in our laboratory utilizing the SS Rag1−⁄− rat, an SS rat lacking functional T and B lymphocytes, demonstrate a clear role for immune mechanisms in the exacerbation of high dietary protein-induced hypertension and renal damage 13 . While decades worth of evidence has revealed the extensive effects of nutrition on all aspects of immunity [42][43][44] , more recent studies have demonstrated postprandial induction of both physiological and pathological inflammatory processes, offering a potential mechanism whereby changes in dietary intake can alter functional phenotypes [45][46][47] .…”

“…Subsequent studies found that the source of protein in the diet was largely responsible for this phenotype in the grain-fed SS rats since substitution of casein in the purified diet with wheat gluten recapitulated the protective phenotype 10 . Furthermore, a high protein (casein) diet exacerbates SS hypertension, which is mediated primarily via immune mechanisms 11,13 .…”

“…The present experiments compared the effect of switching the parental generation to a "protective" diet just prior to conception versus lifelong maintenance of the parents on the same diet. Finally, since immune-dependent mechanisms have been shown to mediate both salt-dependent and protein-dependent elevations in blood pressure and renal damage in the SS rat 11,13 , experiments were also performed to examine the differences in immune cell infiltration and immune signaling in the kidney.…”

Biological Context Linking Hypertension and Higher Risk for COVID-19 Severity

“…Monocytes/macrophages can also scavenge reactive oxygen species (Rosenblat et al, 2013) and have a role in clearing vasoactive peptides such as endothelin-1 (Czopek et al, 2019), influencing local vasomotor tone and blood pressure. Depletion of monocytes/macrophages, or impairing their ability to clear endothelin-1, increases blood pressure over a few days in humans and mice (Guzik et al, 2007;Abais-Battad et al, 2018), particularly in the setting of a pre-existing challenge to blood pressure such as high salt or Ang II infusion. Conversely, T-cells and B-cells depletion are protective, reducing hypertension and vascular free-radical production in experimental models (Guzik et al, 2007;Abais-Battad et al, 2018).…”

“…Depletion of monocytes/macrophages, or impairing their ability to clear endothelin-1, increases blood pressure over a few days in humans and mice (Guzik et al, 2007;Abais-Battad et al, 2018), particularly in the setting of a pre-existing challenge to blood pressure such as high salt or Ang II infusion. Conversely, T-cells and B-cells depletion are protective, reducing hypertension and vascular free-radical production in experimental models (Guzik et al, 2007;Abais-Battad et al, 2018). Thus, these cells of the adaptive immune system appear to be "pro-hypertensive" and experimentally, re-population of the T-cell pool restores the full hypertensive response to chronic Ang II infusion (Fehrenbach et al, 2020).…”