Toll-like Receptor 4 (TLR4) Promotes Dahl Salt-Sensitive Hypertension and Renal Damage in a Non-Immune Mediated Mechanism

Previous work has revealed that genetic deletion of the innate immune protein, toll-like receptor 4 (TLR4), on the Dahl Salt-Sensitive background (SS TLR4-/- ) attenuates mean arterial pressure (SS TLR4-/- : 147.1 ± 3.5 vs. SS: 162.5 ± 4.9 mmHg, p<0.0001, n=10/group) and albuminuria (170.6 ± 27.1 vs. 321.3 ± 62.7 mg/day, p<0.05, n=10/group) in males compared to parental SS male rats after three weeks on a high salt diet. Since TLR4 deletion attenuates IL-1β production in macrophages, subsequent experiments were performed to transplant bone marrow from either SS or SS TLR4-/- male donors into SS recipient males which underwent total body irradiation to ablate their hematopoietic cells (n=12/group). Interestingly, irradiated rats that received TLR4 deficient hematopoietic cells exhibited no difference in blood pressure, albuminuria, or renal inflammation compared to those that received SS bone marrow. This finding was observed despite a clear attenuation of IL-1β production in macrophages isolated from rats receiving SS TLR4-/- bone marrow. These results suggest that the effects of TLR4 on salt-sensitive hypertension and renal damage are not immune-mediated. Since TLR4 is expressed on endothelial and smooth muscle cells, we hypothesized that its role in salt-sensitive hypertension and renal damage may be mediated through vascular mechanisms. Male SS (n=4) and SS TLR4-/- (n=3) rats were subjected to a 3-week high salt (4% NaCl) challenge starting at 9 weeks of age. Urine was collected prior to the switch to the high salt diet and at the conclusion of the study to assess sodium and albumin excretion. Myogenic responses and vascular properties were assessed in isolation middle cerebral arteries (MCAs) and mesenteric arteries (MAs). Pressure-diameter relationships for both arteries were measured over pressures ranging from 40-180 mmHg, and their mechanical properties were recorded. SS TLR4-/- rats demonstrated attenuated albuminuria at the conclusion of the high salt challenge in comparison with SS rats (63.2 ± 5 vs. 174.5 ± 6 mg/day, p<0.05). The myogenic response of the MCAs from SS TLR4-/- rats was significantly impaired compared to SS rats, with trends showing increased myogenic tone, vessel diameters, and distensibility, along with reduced wall thickness, cross-sectional area, and wall-to-lumen ratio. Similarly, a marked increase in vessel diameters and a tendency for enhanced distensibility were observed in MAs. However, no other significant differences in vascular function or mechanical properties were found between the two strains at this age. These findings suggest that TLR4 may play a significant role in the development and pathogenesis of Dahl SS hypertension and renal damage, potentially though vascular mechanisms rather than immune-mediated pathways. Results from the current study indicate that TLR4 may contribute to the alteration of the myogenic response and tone resulting from vascular remodeling. Further investigations are warranted to increase our sample sizes and assess the myogenic response of renal vascular beds. Funding Sources: 23PRE1020121, HL161231, HL166458 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.