Intermittent hypoxia prior to completion of nephrogenesis increases systolic blood pressure and proteinuria after angiotensin II treatment in adult male rats
Authors: Ramirez Lindsey A , Snyder Elizabeth , Marin Terri , Sullivan Jennifer C 
Published: June 2021

Background

Preterm birth (birth prior to 37 weeks gestation) affects ~ 15 million neonates worldwide and complications from preterm birth are the leading cause of death in children under 5 years old. Nephrogenesis is completed at gestational week 36 and an underdeveloped kidney combined with periods of hypoxia, commonly experienced by preterm infants, increases the incidence of acute kidney injury (AKI). AKI increases the likelihood of developing cardiovascular and renal diseases as adults, but it is difficult to observe direct effects of preterm birth on adults because the length of time to reach adulthood spans decades. By using a rodent model that recapitulates hypoxic episodes in preterm infants, we can shorten that time frame and uncover the long‐term effects of low oxygen on the underdeveloped rat kidney. We hypothesized that pups exposed to intermittent hypoxia (IH) prior to the completion of nephrogenesis will be more susceptible to a second cardiovascular challenge in adulthood.

Methods

Male Sprague Dawley rat pups (n=6) were exposed to 10 minutes of IH (~10% normobaric O2) 3 times a day with 4 hour intervals between each session during postnatal days (PND) 1–8; nephrogenesis completes on PND 8. Control (Ctrl) pups were not exposed to IH (n=6). 24‐hour metabolic cage data and systolic blood pressure (SBP) measurements were taken at 6, 9, and 12 weeks of age. To determine the response to a cardiovascular challenge, osmotic mini pumps filled with Angiotensin II (Ang II) were implanted at 15 weeks of age (400 ng/kg/min) and 24‐hour metabolic cage data and SBP measurements were taken 2 weeks later.

Results

Prior to Ang II treatment, Ctrl and IH rats had similar SBP (mean difference= 3.7 mmHg, p> .05). After Ang II treatment, SBP in Ctrl rats increased from 161.2 ± 7.1 mmHg to 177.8 ±7.8 mmHg (p< .05) and there was a greater increase in SBP for IH rats from 164.9 ± 6 mmHg to 224.7 ±15.5 mmHg (p< .05). Following Ang II treatment, IH rats had higher SBP compared to Ctrl rats (p< .05). Ang II treatment increased proteinuria in Ctrl rats from 25.8 ± 2.3 mg/day to 66.6 ±25.8 mg/day (p< .05) and there was a greater increase in IH rats from 29.2 ±4.5 to 127.7 ± 30.6 (p< .05). Proteinuria was similar in both groups before and after treatment (p> .05).

Discussion

Greater increases in SBP and proteinuria in the IH rats after Ang II treatment suggests that application of this IH protocol prior to nephrogenesis completion increases susceptibility to a cardiovascular challenge in adulthood. This is significant because we can study the long‐term effects of hypoxia prior to the completion of nephrogenesis in a condensed amount of time. To further determine the consequences of periods of hypoxia prior to nephrogenesis completion, we plan to examine kidney structure and vessel density using histology and implant telemeters for more accurate blood pressure readings.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.