A new model for studying X-chromosome effects in male Dahl salt-sensitive rats

The Dahl salt-sensitive (SS) rat is a model of hypertension that replicates important subclinical features of human salt sensitivity, including blood pressure (BP) changes and end-organ damage in response to a high salt (HS) diet challenge. In rats, multiple sex determining region Y ( Sry ) gene paralogues encoding for SRY protein crucial for male-typical development, are located on the Y chromosome, obscuring our understanding the relative contributions of X-chromosome gene dosage to male hypertension phenotypes in this model. To investigate the impact of X-chromosome complement on male salt-sensitive hypertension, a transgene harboring the Sry1, Sry4a, and Sry3c genes was inserted into the Dahl SS strain on an autosome. Natural mating of XY SryTg males results in male offspring with XY, XX SryTg , or XY SryTg genotypes. We hypothesized that this model can be used to segregate the role of X-chromosome gene dosage in the male hypertensive phenotypes of the SS rat. Male rats of each genotype were challenged with an 8.0% NaCl diet beginning at ten weeks of age for two weeks. Body weight was tracked, and urinalysis and kidney histology were assessed at the end of the study. While no differences in bodyweight between XY and XX SryTg males were observed, XY SryTg were larger than XX SryTg gonadal males from 4-12 weeks of age (week seven body weight: XY=208±8, XX SryTg =183±3, XY SryTg =219±4 g). Albumin and protein excretion trended lower in XY SryTg but were not significantly different by genotype (UAE: XY=274±60, XX SryTg =246±35, XY SryTg =162±18 mg/day; UPE: XY=531±75, XX SryTg =447±46, XY SryTg =362±29 mg/day). No significant differences in heart or kidney weight, or medullary protein casting were observed between male genotype (heart: XY=1.32±0.05, XX SryTg =1.24±0.03, XY SryTg =1.34±0.03 g; kidney: XY=1.91±0.11, XX SryTg =1.83±0.06; XY SryTg =1.87±0.06 g; protein casting: XY=4.24±0.45, XX SryTg =4.01±0.49, XY SryTg =4.38±0.47 %). In summary, X-chromosome complement did not impact indications of heart or renal injury in response to high salt diet in intact male SS rats. Funded by NIH R01 OD030496 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.