Endoplasmic reticulum (ER) stress contributes to acute kidney injury induced by several causes. Kidney dysfunction was shown to be influenced by gender differences. In this study we observed differences in the severity of kidney injury between male and female mice in response to tunicamycin, an ER stress agent. Tunicamycin-treated male mice showed a severe decline in kidney function and extensive kidney damage of proximal tubules in the kidney outer cortex (S1 and S2 segments). Interestingly, female tunicamycin-treated mice did not show a decline in kidney function, and their kidneys showed damage localized primarily to proximal tubules in the inner cortex (S3 segment). Protein markers of ER stress, glucose-regulated protein, and X-box binding protein 1 were also more elevated in male mice. Similarly, the induction of apoptosis was higher in tunicamycin-treated male mice, as measured by the activation of Bax and caspase-3. Testosterone administered to female mice before tunicamycin resulted in a phenotype similar to male mice with a comparable decline in renal function, tissue morphology, and induction of ER stress markers. We conclude that kidneys of male mice are much more susceptible to ER stress-induced acute kidney injury than those of females. Moreover, this sexual dimorphism could provide an interesting model to study the relation between kidney function and injury to a specific nephron segment.

Background Postural tachycardia syndrome (POTS) is a disorder characterized by excessive orthostatic tachycardia and significant functional disability. Previously, we reported that POTS patients have low blood volume and inappropriately low renin activity (PRA) and aldosterone. In this study, we sought to more fully characterize the renin-angiotensin-aldosterone system (RAAS), to gain a better understanding of the pathophysiology of POTS. Objective We prospectively assessed the plasma levels of Angiotensin (Ang) peptides and their relationship to other RAAS components in patients with POTS compared with healthy controls. Methods While on a sodium controlled diet, heart rate (HR), PRA, Ang I, Ang II, Ang (1–7) and aldosterone were measured in POTS patients (n=38) and healthy controls (n=13). Results POTS patients had larger orthostatic increases in HR than controls (52±3 [mean±SEM] bpm vs. 27±6 bpm; P=0.001). Plasma Ang II was significantly higher in POTS patients (43±3 pg/ml vs. 28±3 pg/ml; P=0.006), while plasma Ang I and Ang-(1–7) were similar between groups. Despite the two-fold increase of Ang II, POTS patients trended to lower PRA levels than controls (0.9±0.1 ng/mL/h vs. 1.6±0.5 ng/mL/h, P=0.268) and lower aldosterone levels (4.6±0.8 pg/ml vs. 10.0±3.0 pg/ml; P=0.111). Estimated angiotensin-converting enzyme-2 (ACE2) activity was significantly lower in POTS than controls (0.25±0.02 vs. 0.33±0.03; P=0.038). Conclusions Some patients with POTS have inappropriately high plasma angiotensin II levels, with low estimated ACE2 activity. We propose that these abnormalities in angiotensin regulation may play a key role in the pathophysiology of POTS in some patients.

Background Postural tachycardia syndrome (POTS) is characterized by excessive orthostatic tachycardia and significant functional disability. We have previously found that POTS patients had increases in plasma angiotensin II (Ang II) twice as high as normal subjects despite normal blood pressures. In this study we assess systemic and renal hemodynamic and functional responses to Ang II infusion in patients with POTS compared with healthy controls. Methods and Results Following a 3 day sodium controlled diet, we infused Ang II (3 ng/kg/min) for 1 hour in POTS patients (n=15) and healthy controls (n=13) in the supine position. All study subjects were females with normal blood pressure (BP). Ages were similar for POTS and control subjects (30±2 [mean±SEM] vs. 26±1 years; P=0.11). We measured the changes from baseline mean arterial pressure (MAP), renal plasma flow (RPF), plasma renin activity (PRA), aldosterone, urine sodium and baroreflex sensitivity in both groups. In response to Ang II infusion, POTS patients had a blunted increase compared with control subjects in MAP (10±1 mmHg vs. 14±1 mmHg; P=0.01), and diastolic BP (9±1 mmHg vs. 13±1 mmHg; P=0.01), but not systolic BP (13±2 mmHg vs. 15±2 mmHg; P=0.40). Renal plasma flow (RPF) decreased similarly with Ang II infusion in POTS patients and controls (−166±20 vs. −181±17 mL/min/1.73 kg/m2; P=0.58). Post-infusion, the decrease in PRA (−0.9±0.2 vs. −0.6±0.2 ng/mL/h; P=0.43) and the increase in aldosterone (17±1 vs. 15±2 pg/ml; P=0.34) were similar in POTS and controls. The decrease in urine sodium excretion was similar in both POTS and controls (−49±12 vs. −60±16 mEq/g Cr; P=0.55). The spontaneous baroreflex sensitivity at baseline was significantly lower in POTS compared to healthy controls (10.1±1.2 vs. 16.8±1.5 ms/mmHg, P=0.003) and it was further reduced with Ang II infusion. Conclusions Patients with POTS have blunted vasopressor response to Ang II and impaired baroreflex function. This impaired vasoconstrictive response might be exaggerated with upright posture, and may contribute to the subsequent orthostatic tachycardia that is the hallmark of this disorder.

A control-derived LA voltage cutoff of <1.1 mV for EAVM in SR reveals maLVA, harboring abnormal electrograms, as an independent predictor for recurrences after PVI alone in patients without LVA (< 0.5 mV). Adjunctive maLVA-guided substrate ablation targeting mildly remodeled and potentially arrhythmogenic LA substrate may further improve the long-term outcome of AF ablation.