T-cells regulate albuminuria but not blood pressure or tissue damage in the Dahl SSCD247+/+ rat model of hypertension

Abstract

Previous studies have demonstrated a key role for renal inflammation in the progression of salt-sensitive hypertension (SS-HTN). Pharmacological and genetic inhibition of inflammation blunts the progression of hypertension in several models, including Dahl salt-sensitive (SS) rats. Traditionally, it has been difficult to separate the pathological effects of renal T-cells from those of exposure of the kidney to elevated pressure since the inhibition of renal inflammation results in a reduction in blood pressure, and vice versa. Therefore, improved renal function and reduced injury after the suppression of inflammation may be the result of reduced renal T-cells, reduced blood pressure, or both. In these studies, we took advantage of a loss of protection from SS-HTN in SS rats lacking T-cells, SS CD247-/- rats, to isolate the pathological effects of renal T-cells from those of hypertension on the kidney.Studies were performed on male SS CD247+/+ and SS CD247-/- rats obtained from heterozygous breeders. From birth rats were maintained on a purified control salt diet (CS, 0.4% NaCl) and switched to a high-salt diet (HS, 4.0% NaCl) during experiments.In contrast to previous studies, we found that MAP following 21-days of HS was not significantly different between SS CD247+/+ and SS CD247-/- rats (SS CD247+/+ : 156 ± 2.2 mmHg, n=16 vs SS CD247-/- : 151 ± 2.2mmHg, n=14, p=0.05). Using flow-cytometry we confirmed that the loss of protection from SS-HTN was not due to the reconstitution of T-cells in the SS CD247-/- rats. T-cells were absent in the kidneys of SS CD247-/- rats after 21-days of HS, comprising 0.06 ± 0.015% of live renal cells, compared to 26.08 ± 2.13% in SS CD247+/+ rats (p= 0.006, n=4+7).Despite the equivalent levels of SS-HTN, we found that the SS CD247-/- rats demonstrated significantly lower levels of albuminuria than their wild-type littermates (528 ± 73 mg/g, n=5 vs 963 ± 156 mg/g, n=7, p=0.008). In contrast to the albuminuria, we found that kidney injury, specifically tubular protein casts and glomerular injury, were not significantly different between SS CD247+/+ and SS CD247-/- rats, while there was a significant correlation between these factors and MAP at tissue collection. RNA-sequencing data confirmed this correlation between injury and MAP – only 99 genes differed significantly in the outer medulla of SS CD247-/- and SS CD247+/+ rats, while >4000 genes differed significantly across the range of pressures evaluated.These findings demonstrate that the pathological effects of renal T-cells are primarily manifested in albuminuria and that the effects of pressure substantially outweigh the effects of T-cell infiltration on histologic injury and transcriptomics of the kidney in SS-HTN. R01HL152166. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.