In models of genetic
hypertension, renal tubular dysfunction could be involved in the increased
sodium and water reabsorption. However, the molecular basis for the increased renal
sodium and water retention remains largely undefined in spontaneously hypertensive rats (SHR). We hypothesized that dysregulation of renal
epithelial sodium channels (ENaC),
sodium (
co)transporters, or
aquaporin-2 (AQP2) could be involved in the pathogenesis of
hypertension in SHR. Six-week-old or twelve-week-old SHR and corresponding age-matched Wistar-Kyoto control rats (WKY) were studied. In both SHR groups, systolic blood pressure was markedly increased, whereas urine output,
creatinine clearance, and urinary
sodium excretion were decreased compared with corresponding WKY. Moreover, urine osmolality and urine-to-plasma osmolality ratio were increased compared with WKY. Semiquantitative immunoblotting demonstrated that the
protein abundance of beta- and gamma-subunits of ENaC was increased in the cortex and outer stripe of the outer medulla and inner stripe of the outer medulla (ISOM) in SHR, whereas alpha-ENaC abundance was increased in ISOM. Immunoperoxidase microscopy confirmed the increased labeling of beta-ENaC and gamma-ENaC subunits in the late distal convoluted tubule, connecting tubule, and cortical and outer medullary collecting duct segments. In contrast, subcellular localization of alpha-
ENaC, beta-ENaC, and gamma-ENaC was not changed. Expression of
sodium/hydrogen exchanger type 3,
bumetanide-sensitive Na-K-2Cl cotransporter, and
thiazide-sensitive Na-Cl cotransporter was not altered in SHR. AQP2 levels were increased in the ISOM in SHR, and immunoperoxidase microscopy demonstrated an increased apical labeling of AQP2 in the inner medullary collecting duct in SHR. These results suggest that the increased
protein abundance of ENaC subunits as well as the increased apical targeting of AQP2 may contribute to renal
sodium and water retention observed during the development of
hypertension in SHR.