FIGURE 19.

Proposed mechanisms whereby increased reactive oxygen species (ROS) cause hypertension and renal injury in the Dahl salt-sensitive rat. An imbalance favoring renal medullary ROS in the Dahl salt-sensitive rat would increase Na⁺-K⁺-2Cl⁻ cotransporter type 2 (NKCC2) activity by both direct stimulation and by inhibition of NO synthase type 3 (NOS3). A more active thick ascending limb would decrease Na⁺ delivery to the macula, thereby reducing tubuloglomerular feedback (TGF). These changes would increase glomerular perfusion pressure and filtration rate, which over time would damage the glomerulus, thereby reducing the filtration surface. In addition, because ROS production is regulated by luminal flow in thick ascending limbs, an increase in filtration rate would augment fluid delivery to this segment, perpetuating the injury. Given the link between ROS production, luminal flow, and Na⁺ reabsorption by the thick ascending limb, increased medullary oxidative stress is considered one of the driving forces for the development of salt-sensitive hypertension in the Dahl rat.