Salt-Sensitive Hypertension: Role of renal superoxide

Case Western Reserve University, Cleveland OH

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Abstract

About 25% of Americans have salt-sensitive hypertension. Abnormal salt retention by thick ascending limbs (THALs) can cause this pathology. Flow of the forming urine stimulates THAL NO production by NO synthase 3 (NOS3) which inhibits NaCl reabsorption. Flow also augments O2- synthesis which stimulates Na reabsorption. In normotensive animals, flow-stimulated NO prevents flow-induced increases in O2-. Flow increases THAL NO via activation of TRPV4, increases in intracellular Ca (Cai), and activation of PI3 kinase, Akt and NOS3. However, the mechanotransduction process upstream of TRPV4 is unknown. Our new data show that primary cilia and the glycocalyx are the mechanotransducers. However, the molecular mechanisms by which primary cilia and the glycocalyx transduce flow into TRPV4 activation and THAL NO synthesis are unknown. Estrogen protects the glycocalyx while testosterone has no known effect. Whether there are sex differences in glycocalyx-mediated NO synthesis is unclear. TMEM184A is a newly discovered protein that binds heparin, a glycocalyx component. In endothelial cells, TMEM184A links the glycocalyx to TRPV4 activation and NO production. However, whether TMEM184A plays a similar role in THALs is unknown. Dietary salt increases blood pressure (BP) in both male and female Dahl salt-sensitive rats (SS) but more so in males. We showed that NO synthesis was lower in SS THALs than salt-resistant (SR) tubules when rats are on normal salt, and high salt exacerbated the difference. Although renal oxidative stress is elevated in SS THALs, the reduction in NO is not due to simple scavenging by O2-. Oxidative stress causes glycocalyx shedding and decreases mechanotransduction of flow. However, the roles of the glycocalyx and oxidative stress on mechanotransduction mediated by this organelle in SS THALs have not been studied. In endothelial cells flow enhances NOS3 expression. A high-salt diet increases THAL flow and enhances SR THAL NO synthesis by increasing NOS3 expression, but high salt does not increase NOS3 protein in SS THALs. Whether this is due to glycocalyx shedding is unknown. Our hypothesis is that in THALs flow-stimulated NO synthesis and NOS3 expression depends on the primary cilia displacing the glycocalyx, which activates TMEM184A and TRPV4. Oxidative stress causes glycocalyx shedding in SS THALs, thereby reducing flow-induced NO production, NOS3 expression and urinary Na excretion (UNaV) leading to salt-sensitive hypertension in a sex-dependent manner. Aim 1 hypothesis: Luminal flow bends primary cilia displacing the glycocalyx, activating TMEM184A and TRPV4, thereby stimulating NOS3 translocation and NO synthesis by THALs from normotensive rats. Aim 2 hypothesis: THAL oxidative stress damages the glycocalyx, blunting flow-stimulated Cai, NO synthesis and NO inhibition of NaCl reabsorption, and blocks salt-induced increases in NOS3 protein in a sex-dependent manner. Aim 3 hypothesis: Oxidative stress-induced shedding of the THAL glycocalyx in vivo blunts NO synthesis and UNaV, especially on high salt, causing salt-sensitive hypertension in a sex-dependent manner. Thus, we propose a novel role for the glycocalyx in BP regulation.