Renal HETA/ETB Receptor Disbalance Characterizes Progression to Salt Sensitive Malignant Hypertension in Spontaneous Hypertension
It is unclear why a subgroup of patients with essential hypertension develop salt sensitive hypertension with progression to malignant hypertension and renal failure. We evaluated the role of the renal endothelin (ET)-system in this setting by investigating two animal models with either salt-resistant or salt sensitive spontaneous hypertension. We studied salt resistant spontaneously hypertensive rats (SHR) and salt sensitive stroke-prone spontaneously hypertensive rats (SHRSP) after either sham operation on a normal diet (Sham) or after unilateral nephrectomy and high NaCl loading (NX-NaCl) with 4% NaCl in diet for 6 weeks (n=10, respectively). Systolic blood pressure (SBP) increased only in SHRSP-NX-NaCl compared to SHRSP-Sham (250±6 vs. 172±5 mmHg, p<0.0001) while SBP remained unchanged in SHR-NX-NaCl compared to SHR-Sham. Albuminuria increased 210-fold in SHRSP-NX-NaCl compared to SHRSP-Sham (p<0.0001), but no significant change was observed in SHR-NX-NaCl. In SHRSP-NX-NaCl glomerulosclerosis index, tubulointerstitial damage index, renal ET-1 mRNA expression, and urinary ET-1 excretion were significantly elevated compared to SHRSP (p<0.05, respectively), but no significant changes of these parameters were found in SHR after NX-NaCl. Urinary sodium excretion (UNa) increased in both SHR and SHRSP after NX-NaCl, but UNa was significantly reduced by 60% in SHRSP-NX-NaCl compared to SHR-NX-NaCl (p<0.0001). After NX-NaCl renal ETA and ETB receptor densities, obtained by Scatchard analyses, were elevated in both SHR and SHRSP (ETA: 2.2- and 4.7-fold, ETB: 2.2- and 2.4-fold, p<0.05 respectively). However, ETA increase was significantly more pronounced in SHRSP-NX-NaCl, thus resulting in an 2.1-fold increase of ETA/ETB receptor ratio in SHRSP-NX-NaCl. We conclude that activation of the renal ET system in conjunction with an increased ETA/ETB receptor ratio may contribute to decreased UNa and higher susceptibility for the development malignant hypertension and kidney damage in salt sensitive spontaneous hypertension.