Sex Difference in Autoregulatory Responses of Juxtamedullary Afferent Arterioles Following Ischemia-Reperfusion in Rats.

Renal ischemia-reperfusion (IR) is a major cause of acute kidney injury (AKI). Renal autoregulation protects the kidney from ischemia at low arterial pressure and hyperperfusion at high arterial pressure. Female rats are more protected against AKI than male rats. We reported that IR impaired autoregulatory behavior of afferent arterioles (AA) in male rats 24 hours and 1-week post-IR. We hypothesize that AA autoregulatory control in IR-induced AKI (IR-AKI) is better preserved in female rats compared to males. IR was induced in female rats by bilateral renal arterial clamping for 60 minutes followed by reperfusion for 24 hours or 1 week. Autoregulatory responses were assessed using the in vitro blood-perfused juxtamedullary nephron preparation during step increases in perfusion pressure (PP) from 65 to 170 mmHg at 15 mmHg intervals in sham-operated and IR rats 24 hours and 1-week post-IR. AA from sham rats exhibited pressure-dependent vasoreactivity. Baseline AA diameter averaged 12.1±1.4 µm in shams (n=3) 24 hours post-surgery. Diameter increased to 112±2% of baseline when PP decreased from 100 to 65 mmHg and decreased to 70±6% of baseline when PP increased to 170 mmHg (P<0.05), indicating intact autoregulation. Conversely, baseline diameter in IR rats (n=5) averaged 10.0±1.4 µm and remained relatively unaltered during PP changes averaging between 98-102% (P>0.05) of baseline, indicating impaired autoregulation. Shams 1 week post-IR (n=3) exhibited autoregulatory responses similar to 24-hour shams. Intriguingly, autoregulatory responses normalized within 1 week in female IR rats (n=3) though these rats still maintained increased urine output over 1 week (P<0.05). Diameter increased to 110±4% of baseline at 65 mmHg and decreased to 82±4% at 170 mmHg (P<0.05) of baseline (9.4±1.2 µm, n=3). mRNA expression of NADPH oxidase (NOX) subunits and the inflammatory chemokine (C-C motif) Ligand 2 (CCL2) were measured in isolated preglomerular microvessels (PGMV, n=4-8/group). Only p67 expression in PGMV increased in female IR rats 24 hours post-IR compared to elevation of all three of the NOX subunits (gp91 , p67 , and p47 ) to male IR rats. IR significantly increased CCL2 mRNA expression in female PGMV 7-fold and 3-fold at 24 hours and 1-week post-IR, respectively, compared to shams (P<0.05). mRNA expression increased less in females than males (9-fold at 24 hours and 6-fold at 1 week after IR, respectively). In conclusion, autoregulatory behavior in female rats is significantly blunted, 24 hours post-IR and normalized 1-week post-IR, in contrast, all male IR rats exhibited blunted autoregulatory behavior 24 hours and 1-week post-IR. Increased CCL2 mRNA expression parallels the dimorphism of AA autoregulatory reactivity following IR, suggesting that elevated CCL2 could mediate IR-induced AA autoregulatory dysfunction. Overall, these results suggest a sexual dimorphism in the renal microvascular response to IR injury and that female rats may possess innate protection against IR-AKI.