Clincal Fellow Columbia University Vagelos College of Physicians and Surgeons New York, New York, United States
Background: Humans born preterm have low nephron endowment and an increased risk for hypertension (HTN), yet the pathogenesis of HTN due to nephron deficits is poorly understood. Objective: To test the hypothesis that nephron deficits are an independent risk factor for HTN and that salt intake modifies this response using a new mouse model of congenitally low nephron number (40-60% nephron reduction, named RetUB del mice, Good et al, JCI Insight, 2023). Design/Methods: Male and female control and RetUB del mice (9-10m old) had continuous systolic and diastolic blood pressure (SBP and DBP) monitoring for 72h using radiotelemetric methods. Mice were fed high salt chow (8% NaCl) for 10d before another 72h of BP measurements. We collected blood, urine, and kidneys at the end of the study and analyzed BP with mixed effects models. Results: In females at baseline, control and RetUB del mice had no significant differences in SBP, DBP, or mean arterial pressure (MAP) (n=4 per group). High salt intake resulted in insignificant increases in SBP, DBP and MAP in both groups, but the rise in SBP was significantly greater (excess of 5.8 mmHg, p< 0.001) in RetUB del vs. controls. Similarly, rises in DBP (excess of 4.7 mmHg) and MAP (excess of 5.2 mmHg) were significantly greater in RetUB del vs. controls (p < 0.001). Both groups had normal serum creatinine (Cr), blood urea nitrogen (BUN), hematocrits (Hct), sodium (Na), fractional excretion of sodium (FeNa), and urine Na:Cr. Similarly, in males at baseline, RetUB del and control mice had no significant differences in SBP, DBP or MAP (n=4-6 per group). High salt intake also resulted in insignificant increases in SBP, DBP and MAP in both groups. Although rises in SBP were similar, there was a significantly greater rise in DBP (excess of 2.0 mmHg) and MAP (excess of 0.8 mmHg) in RetUB del vs. controls (p < 0.01). RetUB del males had higher serum Cr, BUN, FeNa and urine Na:Cr, while serum Na and Hct were similar to controls. Morphologically, RetUB del females had focal CKD whereas males showed more widespread CKD changes.
Conclusion(s): RetUB del mice did not have HTN under basal conditions, yet high salt intake caused a greater rise in BP in females. This response is independent of renal function and unlikely attributable to pathological changes of CKD given that males had a more severe CKD phenotype yet less of a rise in BP. Our results reveal sex dimorphisms in salt response and emphasize the need for lifestyle modifications in humans born preterm. Further studies will focus on mechanisms of sex dimorphisms in HTN.
