T helper cell polarity determines salt sensitivity and hypertension development.

High-salt intake is known to induce pathogenic T helper (Th) 17 cells and hypertension, but contrary to what is known, causes hypertension only in salt-sensitive (SS) individuals. Thus, we hypothesized that Th cell polarity determines salt sensitivity and hypertension development. Cultured splenic T cells from Dahl SS and salt-resistant (SR) rats subjected to hypertonic salt solutions were evaluated via ELISA, flow cytometry, immunocytochemistry and RT-qPCR. Seven-week-old SS and SR rats were fed a chow (CD) or high-salt diet (HSD) for 4 weeks, with weekly measurements of systolic blood pressure. The relaxation response of the aorta rings to the cumulative addition of acetylcholine was measured ex vivo. In these experimental animals, the Th cell polarity (Th17 and T regulatory [Treg]), the expression of Th17- or Treg-related genes, and the enrichment of the transcription factors RORγt and FOXP3 on the target gene promoter regions were determined via flow cytometry, RT-qPCR, and chromatin immunoprecipitation. Hypertonic salt solution induced Th17 and Treg cell differentiation in cultured splenic T cells isolated from SS and SR rats, respectively. HSD induced hypertension, endothelial dysfunction and proinflammatory Th17 cell differentiation only in SS rats. The enrichment of RORγt on the promoter regions of Il17a and Il23r increased their expression only in SS rats. Regardless of HSD, SR rats remained normotensive with Treg polarity, causing high Treg-related gene expressions (Il10, Cd25 and Foxp3). This study demonstrated that Th cell polarity determines salt sensitivity and drives hypertension development. SR rats were protected from HSD-associated hypertension via anti-inflammatory Treg polarity.

Dahl Salt-Resistant Rat Is Protected against Hypertension during Diet-Induced Obesity.

A high-fat diet (HFD) frequently causes obesity-induced hypertension. Because Dahl salt-resistant rats are protected against hypertension after high-salt or high-fructose intake, it is of interest whether this model also protects against hypertension after diet-induced obesity. We tested the hypothesis that Dahl salt-resistant rat protects against hypertension during diet-induced obesity. Dahl salt-sensitive (SS) and Dahl salt-resistant (SR) rats were fed a HFD (60% fat) or a chow diet (CD; 8% fat) for 12 weeks. We measured blood pressure using the tail-cuff method. The paraffin sections of thoracic perivascular adipose tissue (tPVAT) were stained with hematoxylin/eosin and trichrome. The expression of genes in the tPVAT and kidneys were measured by reverse transcription-quantitative polymerase chain reaction. The HFD induced hypertension in SS (p < 0.01) but not SR rats, although it increased body weight gain (p < 0.05) and tPVAT weight (p < 0.01) in both rats. The HFD did not affect the expression of genes related to any of the adipocyte markers in both rats, although SR rats had reduced beige adipocyte marker Tmem26 levels (p < 0.01) and increased anti-inflammatory cytokine adiponectin (p < 0.05) as compared with SS rat. The HFD did not affect the mRNA expression of contractile factors in the tPVAT of SS and SR rats. SR rats are protected against hypertension during diet-induced obesity. This result implies that the genetic trait determining salt sensitivity may also determine fructose and fat sensitivity and that it is associated with the prevention of hypertension.

Dahl salt-resistant rats are protected against angiotensin II-induced hypertension.

Angiotensin II is a potent endogenous vasoconstrictor that induces oxidative stress in hypertensive rodent models. Dahl salt-resistant (SR) rats are protected against hypertension after high salt or high fructose intake. However, whether these rats are also protected against angiotensin II-mediated hypertension has not been investigated. Dahl salt-sensitive (SS) and SR rats were infused with angiotensin II (10 or 50 ng/kg/min) or vehicle via a mini-osmotic pump for 2 weeks. Blood pressure was measured using the tail-cuff method. Paraffin sections of the thoracic aortas and kidneys were stained using hematoxylin/eosin or Masson trichrome. Renal gene expression was measured using reverse transcription-quantitative polymerase chain reaction. Angiotensin II (50 ng/kg/min) induced hypertension in SS rats, but not in SR rats, although low doses of angiotensin II (10 ng/kg/min) transiently increased blood pressure in SS rats. Angiotensin II (50 ng/kg/min) did not induce morphological changes in the aortic walls or kidneys. Angiotensin II (50 ng/kg/min) induced the expression of At1rb, Nox2, Il-17ra, Il-23r, Tgf-ß, Il-1ß and Il-6 in SS rats, but not in SR rats. In conclusion, SR rats were protected against angiotensin II-induced hypertension. This result implies that the genetic trait that determines salt sensitivity may also determine susceptibility to hypertension in response to vasoconstrictors.