Pseudohypoaldosteronism

The epithelial sodium channel (ENaC) is essential for mediating sodium absorption in several epithelia. Its impaired function leads to severe disorders, including pseudohypoaldosteronism type 1 and respiratory distress. Therefore, pharmacological ENaC activators have potential therapeutic implications. Previously, a small molecule ENaC activator (S3969) was developed. So far, little is known about molecular mechanisms involved in S3969-mediated ENaC stimulation. Here, we identified an S3969 binding site in human ENaC by combining structure-based simulations with molecular biological methods and electrophysiological measurements of ENaC heterologously expressed in Xenopus laevis oocytes. We confirmed a previous observation that the extracellular loop of β-ENaC is essential for ENaC stimulation by S3969. Molecular dynamics (MD) simulations predicted critical residues in the thumb domain of β-ENaC (Arg388, Phe391, and Tyr406) that coordinate S3969 within a binding site localized at the β-γ-subunit interface. Importantly, mutating each of these residues reduced (R388H; R388A) or nearly abolished (F391G; Y406A) the S3969-mediated ENaC activation. MD simulations also suggested that S3969-mediated ENaC stimulation involved a movement of the α5 helix of the thumb domain of β-ENaC away from the palm domain of γ-ENaC. Consistent with this, the introduction of two cysteine residues (βR437C - γS298C) to form a disulfide bridge connecting these two domains prevented ENaC stimulation by S3969 unless the disulfide bond was reduced by DTT. Finally, we demonstrated that S3969 stimulated ENaC endogenously expressed in cultured human airway epithelial cells (H441). These new findings may lead to novel (patho-)physiological and therapeutic concepts for disorders associated with altered ENaC function.

No validated score is available for the prediction of return to sport (RTS) after proximal hamstring avulsion (PHA) surgery.

To validate a new assessment tool for patients after PHA surgery: the Parisian Hamstring Avulsion Score (PHAS).

Cohort study (Diagnosis); Level of evidence, 3.

All patients at our clinic who had surgery for PHA between January 2015 and March 2018 were included in this study. A suspected clinical diagnosis of PHA was confirmed by magnetic resonance imaging. PHA was repaired by surgical reinsertion with suture anchors. Minimum postoperative follow-up was 2 years, and the PHAS, University of California, Los Angeles (UCLA), score, and Tegner score were used. The PHAS is a patient-reported outcome measure, evaluating the effect of PHA injury with 9 items. It was validated by calculating its psychometric properties, and then correlation analysis was performed to determine the relationship between the PHAS, UCLA score, and Tegner score. Cutoff values for the prediction of RTS were determined.

A prospective case series study was performed. A total of 156 patients were included. Median age (first quartile; third quartile) was 54.2 years (44.7 years; 61.3 years), and the mean ± SD time of the final follow-up was 69 ± 11.6 months. Two years after surgery, 66.7% (n = 104) of patients were able to RTS. A strong correlation was noted between all 3 scores at 1 year postoperatively. Overall internal consistency was high, with a Cronbach alpha coefficient of 0.86. The intraclass correlation coefficient was 0.96, showing excellent reliability. The minimal detectable change was 12.9. No patients reached the maximum score at 2 years. Analysis of the receiver operating characteristic curves of the 3 scores at postoperative 9 months in relation to the RTS at 1 and 2 years showed area under the curve values of >0.7, indicating significant discriminant capacity for the RTS. A PHAS cutoff value of 86 at 9 months for the prediction of RTS at postoperative 1 year had a sensitivity of 65.6% (95% CI, 53.7%-77.5%) and a specificity of 81.4% (95% CI, 69.8%-93%).

PHAS is a valid and reliable tool for follow-up after PHA surgery. It also offers a simple way to predict RTS.

Hypertension, commonly known as high blood pressure, is a widespread health condition affecting a large number of individuals across the globe. Although lifestyle choices and environmental factors are known to have a significant impact on its development, there is growing recognition of the influence of genetic factors in the pathogenesis of hypertension. This review specifically focuses on the hereditary causes of hypertension that are associated with increased sodium transport through the thiazide-sensitive NaCl cotransporter (NCC) or amiloride-sensitive epithelial sodium channel (ENaC), crucial mechanisms involved in regulating blood pressure in the kidneys. By examining genetic mutations and signaling molecules linked to the dysregulation of sodium transport, this review aims to deepen our understanding of the hereditary causes of hypertension and shed light on potential therapeutic targets.

Liddle syndrome (LS) is a genetic disorder that typically manifests early in life and is characterized by hypertension, hypokalemic metabolic alkalosis, hyporeninemia, and suppressed aldosterone secretion. This condition is primarily caused by gain-of-function mutations in ENaC. In contrast, Pseudohypoaldosteronism type II (PHAII) is marked by hyperkalemia and hypertension, alongside other clinical features such as hyperchloremia, metabolic acidosis, and suppressed plasma renin levels. PHAII results from overactivations of NCC, brought about by gain-of-function mutations in its upstream signaling molecules, including WNK1 (with no lysine (K) 1), WNK4, Kelch-like 3 (KLHL3), and cullin3 (CUL3).

NCC and ENaC are integral components, and their malfunctions lead to disorders like LS and PHAII, hereditary causes of hypertension. Current treatments for LS involve ENaC blockers (e.g., triamterene and amiloride) in conjunction with low-sodium diets, effectively normalizing blood pressure and potassium levels. In PHAII, thiazide diuretics, which inhibit NCC, are the mainstay treatment, albeit with some limitations and potential side effects. Ongoing research in developing alternative treatments, including small molecules targeting key regulators, holds promise for more effective and tailored hypertension solutions.