Proximal Tubule-Specific Deletion of the NHE3 (Na+/H+ Exchanger 3) in the Kidney Attenuates Ang II (Angiotensin II)-Induced Hypertension in Mice.

The present study directly tested the hypothesis that the NHE3 (Na+/H+ exchanger 3) in the proximal tubules of the kidney is required for the development of Ang II (angiotensin II)-induced hypertension using PT-Nhe3-/- (proximal tubule-specific NHE3 knockout) mice. Specifically, PT-Nhe3-/- mice were generated using the SGLT2-Cre/Nhe3loxlox approach, whereas Ang II-induced hypertension was studied in 12 groups (n=5-12 per group) of adult male and female wild-type (WT) and PT-Nhe3-/- mice. Under basal conditions, systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure were significantly lower in male and female PT-Nhe3-/- than WT mice (P<0.01). A high pressor, 1.5 mg/kg per day, intraperitoneal or a slow pressor dose of Ang II, 0.5 mg/kg per day, intraperitoneal for 2 weeks significantly increased systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure in male and female WT mice (P<0.01), but the hypertensive response to Ang II was markedly attenuated in male and female PT-Nhe3-/- mice (P<0.01). Ang II impaired the pressure-natriuresis response in WT mice, whereas proximal tubule-specific deletion of NHE3 improved the pressure-natriuresis response in Ang II-infused PT-Nhe3-/- mice (P<0.01). AT1 receptor blocker losartan completely blocked Ang II-induced hypertension in both WT and PT-Nhe3-/- mice (P<0.01). However, inhibition of nitric oxide synthase with L-NG-Nitroarginine methyl ester had no effect on Ang II-induced hypertension in WT or PT-Nhe3-/- mice (not significant). Furthermore, Ang II-induced hypertension was significantly attenuated by an orally absorbable NHE3 inhibitor AVE0657. In conclusion, NHE3 in the proximal tubules of the kidney may be a therapeutical target in hypertension induced by Ang II or with increased NHE3 expression in the proximal tubules.

Genetic and genomic evidence for an important role of the Na+/H+ exchanger 3 in blood pressure regulation and angiotensin II-induced hypertension.

The sodium (Na+)/hydrogen (H+) exchanger 3 (NHE3) and sodium-potassium adenosine triphosphatase (Na+/K+-ATPase) are two of the most important Na+ transporters in the proximal tubules of the kidney. On the apical membrane side, NHE3 primarily mediates the entry of Na+ into and the exit of H+ from the proximal tubules, directly and indirectly being responsible for reabsorbing ~50% of filtered Na+ in the proximal tubules of the kidney. On the basolateral membrane side, Na+/K+-ATPase serves as a powerful engine driving Na+ out of, while pumping K+ into the proximal tubules against their concentration gradients. While the roles of NHE3 and Na+/K+-ATPase in proximal tubular Na+ transport under in vitro conditions are well recognized, their respective contributions to the basal blood pressure regulation and angiotensin II (ANG II)-induced hypertension remain poorly understood. Recently, we have been fortunate to be able to use genetically modified mouse models with global, kidney- or proximal tubule-specific deletion of NHE3 to directly determine the cause and effect relationship between NHE3, basal blood pressure homeostasis, and ANG II-induced hypertension at the whole body, kidney and/or proximal tubule levels. The purpose of this article is to review the genetic and genomic evidence for an important role of NHE3 with a focus in the regulation of basal blood pressure and ANG II-induced hypertension, as we learned from studies using global, kidney- or proximal tubule-specific NHE3 knockout mice. We hypothesize that NHE3 in the proximal tubules is necessary for maintaining basal blood pressure homeostasis and the development of ANG II-induced hypertension.

Proximal Tubule-Specific Deletion of the NHE3 (Na+/H+ Exchanger 3) Promotes the Pressure-Natriuresis Response and Lowers Blood Pressure in Mice.

The present study directly tested the hypothesis that deletion of the NHE3 (Na+/H+ exchanger 3) selectively in the proximal tubules of the kidney lowers basal blood pressure by increasing the pressure-natriuresis response in mice. Adult male and female, age-matched wild-type (WT) littermates and proximal tubule-specific NHE3 knockout mice (PT- Nhe3-/-; n=6-16 per group) were studied for (1) basal phenotypes of electrolytes and pH, blood pressure, and kidney function; (2) the pressure-natriuresis response using the mesenteric, celiac, and abdominal arterial occlusion technique; and (3) the natriuretic responses to acute saline expansion (0.9% NaCl, 10% body weight, intraperitoneal) or 2-week of 2% NaCl diet. Under basal conditions, PT- Nhe3-/- mice showed significantly lower systolic, diastolic, and mean arterial blood pressure ( P<0.01) than WT mice ( P<0.01). PT- Nhe3-/- mice also exhibited significantly greater diuretic ( P<0.01) and natriuretic responses than WT mice ( P<0.01), without altering 24-hour fecal Na+ excretion, plasma pH, Na+, and bicarbonate levels. In response to increased renal perfusion pressure by 30 mm Hg, the pressure-natriuresis response increased 5-fold in WT mice ( P<0.01), but it increased 8-fold in PT- Nhe3-/- mice ( P<0.01). In response to 10% acute saline expansion or 2-week 2% NaCl diet, more pronounced natriuretic responses were demonstrated in PT- Nhe3-/- than WT mice ( P<0.01). Our results support the scientific premise and physiological relevance that NHE3 in the proximal tubules plays an essential role in maintaining basal blood pressure homeostasis, and genetic deletion of NHE3 selectively in the proximal tubules of the kidney lowers blood pressure by increasing the pressure natriuretic response.

Intratubular and intracellular renin-angiotensin system in the kidney: a unifying perspective in blood pressure control.

The renin-angiotensin system (RAS) is widely recognized as one of the most important vasoactive hormonal systems in the physiological regulation of blood pressure and the development of hypertension. This recognition is derived from, and supported by, extensive molecular, cellular, genetic, and pharmacological studies on the circulating (tissue-to-tissue), paracrine (cell-to-cell), and intracrine (intracellular, mitochondrial, nuclear) RAS during last several decades. Now, it is widely accepted that circulating and local RAS may act independently or interactively, to regulate sympathetic activity, systemic and renal hemodynamics, body salt and fluid balance, and blood pressure homeostasis. However, there remains continuous debate with respect to the specific sources of intratubular and intracellular RAS in the kidney and other tissues, the relative contributions of the circulating RAS to intratubular and intracellular RAS, and the roles of intratubular compared with intracellular RAS to the normal control of blood pressure or the development of angiotensin II (ANG II)-dependent hypertension. Based on a lecture given at the recent XI International Symposium on Vasoactive Peptides held in Horizonte, Brazil, this article reviews recent studies using mouse models with global, kidney- or proximal tubule-specific overexpression (knockin) or deletion (knockout) of components of the RAS or its receptors. Although much knowledge has been gained from cell- and tissue-specific transgenic or knockout models, a unifying and integrative approach is now required to better understand how the circulating and local intratubular/intracellular RAS act independently, or with other vasoactive systems, to regulate blood pressure, cardiovascular and kidney function.

Dobutamine Therapy is Associated with Worse Clinical Outcomes Compared with Nesiritide Therapy for Acute Decompensated Heart Failure: A Systematic Review and Meta-Analysis.

BACKGROUND: Inotropes and natriuretic peptides are essential components of current therapeutic options for acute decompensated heart failure (ADHF). This systematic review examines the therapeutic effectiveness of dobutamine and brain natriuretic peptide, nesiritide, in reducing mortality and readmission rates for ADHF treatment. METHODS: Published studies related to dobutamine and nesiritide therapy in ADHF were identified via an exhaustive search of scientific literature databases. The identified studies, published between 2002 and 2012, were carefully screened based on our predefined inclusion criteria. Selected studies were pooled, and odds ratios (ORs) and 95% confidence intervals (95% CI) for each outcome were calculated. Subgroup analysis was conducted to assess the influence of ethnicity on the study outcome. RESULTS: Seven cohort studies were selected for this meta-analysis. These seven studies included 959 ADHF patients who underwent nesiritide treatment and 1748 ADHF patients who received dobutamine therapy. Our meta-analysis revealed a significantly lower survival rate in dobutamine-treated patients compared with nesiritide-treated patients (OR 0.48, 95% CI 0.36-0.63, P < 0.001). Additionally, a markedly higher readmission rate was associated with dobutamine treatment compared with nesiritide treatment (OR 0.52, 95% CI 0.36-0.73, P < 0.001). A stratified analysis based on ethnicity revealed a significantly lower survival in dobutamine-treated ADHF patients in Caucasian and mixed populations compared with nesiritide treatment (Caucasian: OR 0.60, 95% CI 0.38-0.94, P = 0.024; Mixed: OR 0.38, 95% CI 0.26-0.56, P < 0.001). However, a similar association was not detected in Asian populations (P = 0.738). Further, dobutamine-treated ADHF patients displayed higher readmission rates than did nesiritide-treated patients in both Caucasian and mixed-race populations (all P < 0.05). CONCLUSIONS: Our study suggests that dobutamine therapy is associated with poorer outcomes, with higher in-hospital mortality rates and increased readmission rates compared with nesiritide therapy in ADHF patients. Thus, current treatment strategies need to be redesigned for better outcomes.