DISTINCT PATTERNS OF RENAL AUTOREGULATORY IMPAIRMENT IN RAT MODELS SUSCEPTIBLE TO HYPERTENSION-INDUCED RENAL INJURY

Renal autoregulation protects glomeruli from hypertensive injury, and defects in autoregulation are attributed to increased susceptibility. Impaired autoregulation has previously been detected in models such as Sprague–Dawley (SD) rats with 3/4 renal mass reduction (RKNX) and Dahl salt-sensitive (SS) rats. Recent unpublished data from our lab demonstrates that both RKNX and Dahl SS rats have similar levels of susceptibility to hypertension-induced renal injury. In contrast, Spontaneously Hypertensive (SHR) and stroke-prone SHR (SHRsp) rats exhibit intact autoregulation and are protected (PMID: 23132368). However, most studies of autoregulation in these models have used anesthetized rats, which significantly limits translational relevance. Here, we examined the dynamics of renal autoregulation in conscious, chronically instrumented SD, RKNX, Dahl SS, SHR, and SHRsp rats.

We analyzed historical blood pressure (BP) and renal blood flow (RBF) data from SD (n=10), RKNX (n=15), SHR (n=17), and SHRsp (n=20) rats (PMID: 31792155; 15827345) and collected new data from Dahl SS (n=14) rats. All rats (male, 10- to 13-week-old) were instrumented with a transit-time RBF probe and BP radiotelemeter. After one week of recovery, BP and RBF were sampled (500 Hz) over 1-4 days in the conscious state. Short-segment autoregulatory indices (SSARIs) (PMID: 31792155) quantified the kinetics (the index at 2.5sec, capturing the initial speed of the autoregulatory response) and magnitude (the index at 20sec, assessing whether complete RBF autoregulation was achieved) of responses to spontaneous BP fluctuations ≥±5 mmHg. Group and segment effects were analyzed by 2-way repeated measures ANOVA with Tukey’s post hoc test. Data are mean±SE, and P<0.05 was considered statistically significant.

SHR and SHRsp showed rapid, complete autoregulatory responses by 2.5sec, which were faster (P<0.05) than SD (Fig. 1). Dahl SS responses were similar to SD at 2.5sec and faster (P<0.05) than RKNX (Fig. 2). However, while SD and RKNX achieved complete autoregulation by 20sec, Dahl SS failed to reach full magnitude, with no significant difference between 2.5- and 20-sec segments.

Distinct autoregulatory defects were observed in susceptible models (RKNX and Dahl SS rats), both of which display nearly identical enhanced susceptibility to hypertension-induced renal injury. RKNX exhibited slowed kinetics but ultimately achieved complete RBF autoregulatory compensation, whereas Dahl SS exhibited normal initial responses but incomplete compensation. In contrast, resistant SHR and SHRsp exhibited rapid, complete RBF autoregulatory responses. These findings indicate that different patterns of impaired RBF autoregulatory responses to spontaneous BP fluctuations are associated with a similar level of susceptibility to hypertension-induced renal injury. Consequently, these results suggest that SSARIs, by identifying kinetic and magnitude defects in autoregulation, may be able to predict susceptibility. Our long-term goal is to utilize SSARI and other analytical methods to assess RBF autoregulation in clinical populations, which would help identify those at greatest risk of CKD progression and enable tailored treatment strategies.