Oxidative stress induces BH4 deficiency in male, but not female, SHR

Abstract

We previously published that female spontaneously hypertensive rats (SHR) have significantly greater nitric oxide (NO) bioavailability and NO synthase (NOS) enzymatic activity in the renal inner medulla (IM) compared with age-matched males, although the mechanism responsible remains unknown. Tetrahydrobiopterin (BH4) is a critical cofactor required for NO generation, and decreases in BH4 as a result of increases in oxidative stress have been implicated in the pathogenesis of hypertension. As male SHR are known to have higher levels of oxidative stress compared with female SHR, we hypothesized that relative BH4 deficiency induced by oxidative stress in male SHR results in lower levels of NOS activity in renal IM compared with females. Twelve-week-old male and female SHR were randomized to receive tempol (30 mg/kg/day via drinking water) or vehicle for 2 weeks. Tempol treatment did not affect blood pressure (BP) in either sex, but reduced peroxynitrite levels only in males. Females had more total biopterin, dihydrobiopterin (BH2), and BH4 levels in renal IMs than males, and tempol treatment eliminated these sex differences. Females had greater total NOS activity in the renal IM than males, and adding exogenous BH4 to the assay increased NOS activity in both sexes. This sex difference in total NOS and the effect of exogenous BH4 were abolished with tempol treatment. We conclude that higher oxidative stress in male SHR results in a relative deficiency of BH4 compared with females, resulting in diminished renal NOS activity in the male.

Sex differences in hypertension: lessons from spontaneously hypertensive rats (SHR)

“…Indeed, treatment with the NADPH oxidase inhibitor apocynin attenuated Ang II-induced increases in BP only in male SHR, thereby abolishing the sex difference in the Ang II-BP response [ 11 ]. However, treatment with apocynin alone for 1 week had no effect on BP in male or female SHR and treatment with the SOD mimetic tempol for 2 weeks does not alter baseline BP in male or female SHR [ 72 ]. Tempol treatment with for 6 weeks reduced BP only in male SHR [ 13 ] and terminal BP measured via femoral catheter indicated a decrease in BP in only male SHR following 7 days treatment with apocynin [ 76 ].…”

“…NO is produced by the enzyme NOS, and there are three NOS isoforms: NOS1 (neuronal NOS, nNOS), NOS2 (inducible NOS, iNOS) and NOS 3 (endothelial NOS, eNOS) [ 85 ]. Excess superoxide preferentially binds NO resulting in decrease in NO bioavailability and the production of peroxynitrite [ 21 , 70 , 72 ]. Decreases in NO bioavailability contribute to endothelial dysfunction and the progression of cardiovascular disease [ 70 ].…”

“…Tetrahydrobiopterin (BH 4 ) is a critical cofactor required for NO generation, and decreases in BH 4 as a result of increases in oxidative stress have been implicated in the pathogenesis of hypertension [ 72 ]. Indeed, we found higher oxidative stress in male SHR results in a relative deficiency of BH 4 compared with females, resulting in diminished renal NOS activity in male SHR [ 72 ]. Therefore, female SHR have both greater NO production and less scavenging of NO resulting in greater NO bioavailability.…”

Chronic exposure to arsenic and high fat diet induces sex-dependent pathogenic effects on the kidney

“…Several studies have reported sex-specific differences in renal responses to environmentally-induced oxidative stress in mice. These differences may be a consequence of gender-related differences in the activities of oxidative stress response enzymes [39][40][41].…”

Losartan through Hsp70 Avoids Angiotensin II Induced Mesenchymal Epithelial Transition Proximal Tubule Cells from Spontaneously Hypertensive Rats

“…Spontaneously Hypertensive Rats (SHR) and Wistar-Kyoto (WKY) male rats (8-10 weeks old) were used due to the greater levels of oxidative stress of male SHR compared with female SHR. In this regards, Gillis et al demonstrated that higher oxidative stress in male SHR conduces to a deficiency of Tetrahydrobiopterin (BH 4 ), a critical cofactor required for NO generation, resulting in diminished renal NOS activity [23]. Indirect systolic blood pressure was measured by the tail cuff method prior to perform the experiments, using a pulse sensor photoelectric CCP model in a Grass polygraph model 7 equipped with a 7P8 pre-amplified (Grass Medical Instruments).…”