Pharmacological inhibition of the chloride-bicarbonate exchanger pendrin with PDSinh-C01 potentiates the diuretic action of furosemide in healthy mice. Because pendrin contributes to acid-base regulation and blood pressure control, it may represent an attractive therapeutic target in chronic kidney disease (CKD). We investigated whether this pendrin inhibitor improves metabolic acidosis and salt-sensitive hypertension in the 5/6 nephrectomy (5/6Nx) model of CKD. Seven-week-old female Sprague Dawley rats underwent 5/6Nx and implantation of telemetry devices for blood pressure monitoring. All animals received a high-salt (2% NaCl) diet and were randomized (n = 7-9/group) to daily subcutaneous injections for three days of vehicle, PDSinh-C01 (10 mg/kg), furosemide (6 mg/kg), or their combination. The 5/6Nx model recapitulated key features of CKD, including reduced eGFR, hypertension, proteinuria, and hyperchloremic metabolic acidosis. Combination therapy produced the greatest reduction in mean arterial pressure (-11 ± 2 mmHg) compared with vehicle (-3 ± 2 mmHg), furosemide (-6 ± 1 mmHg), or pendrin inhibitor alone (-6 ± 2 mmHg). Furosemide and combination therapy increased urine volume at 6h, whereas only combination therapy increased urine volume at 24h. After three days, the pendrin inhibitor alone and combination therapy increased venous bicarbonate concentrations compared with vehicle (24.5 ± 2.1 and 24.3 ± 1.4 vs. 21.4 ± 1.4 mmol/l). In conclusion, PDSinh-C01 combined with furosemide improves salt-sensitive hypertension in CKD, while PDSinh-C01 alone and in combination with furosemide ameliorates metabolic acidosis. These findings support pendrin as a regulator of electrolyte and acid-base balance and as a potential therapeutic target in CKD.

Linking the distinctive structural and functional properties of lipids belonging to different signaling classes is a frontier of physiology. The present minireview focuses on the endocannabinoidome phospholipase NAPE-PLD, which has bile acids (BAs) as structural cofactors at membrane interface and generates bioactive N-acylethanolamines (NAEs) that promote pleiotropic effects. NAPE-PLD is thus at the crossroads of both their physiological functions, an area of ongoing research. The wide internal channel of NAPE-PLD facilitates the transmembrane transport of pyridoxal 5'-phosphate (PLP) and can support the activity of PLP-dependent enzymes in mitochondria, peroxisome and other subcellular compartments. Recent insights demonstrate that drugs and agents that stabilize NAPE-PLD can control blood pressure, vascular resistance and cardiovascular morbidity in clinics, offering new perspectives on the interaction between NAEs and BAs in cardiometabolic and neurological disorders.

Regular physical activity elicits coordinated molecular adaptations across skeletal muscle, the cardiovascular system, metabolic organs and the brain, underpinning improvements in performance and cardiometabolic health. While classical signaling pathways such as AMPK-PGC‑1α, Ca[2+]/calcineurin, and mTORC1 have been extensively characterized, long non-coding RNAs (lncRNAs) have recently emerged as key regulators of exercise-induced remodeling. Here, we synthesize current evidence on lncRNAs as molecular mediators of exercise adaptations, drawing on mechanistic studies and systems-level transcriptomics. In skeletal muscle, the exercise-induced lncRNAs CYTOR and TUG1 modulate fast-twitch myogenesis, mitochondrial function and fiber-type specification. In the heart, CPhar, lncExACT1 and Mhrt779 discriminate physiological from pathological hypertrophy and encode antihypertrophic "memory," whereas endothelial NEAT1 integrates aerobic training with m[6]A-modulated pyroptosis and atheroprotection. MALAT1 mediates neuroprotection after exercise preconditioning in ischemia/reperfusion models. Omics and network analyses reveal highly modality-, tissue- and cell-type-specific lncRNA programs during human training and across multiple organs. Emerging clinical data support circulating lncRNAs such as MALAT1 and HOTTIP as candidate biomarkers of vascular function and training adaptation. Collectively, lncRNAs constitute a hidden regulatory layer that shapes the quality, magnitude and persistence of exercise-induced adaptations. However, mechanistic evidence is currently limited to a small number of "flagships" lncRNAs, and non-muscle tissues and inter-organ communication remain underexplored. Priorities include functional validation of atlas-derived candidates, dissection of exerkine lncRNAs, and integration of lncRNA biology into precision exercise medicine.

Acid-sensing ion channels (ASICs) are widely recognized as proton (H[+])-gated cation channels that respond to extracellular acidification associated with pathological states such as ischemia, inflammation, and epilepsy. However, an emerging body of evidence compels a broader conceptual reframing: ASICs function as dynamic sensors of metabolic state, integrating real-time signals of neural activity, including CO2-derived H[+], lactate, and nano-domain pH transients, to regulate neuronal excitability and intercellular communication. Here, we review the mechanisms by which activity-dependent pH shifts arise in the brain, how lactate potentiates ASIC gating through divalent-cation chelation and direct channel modulation, and how the tripartite neuron-astrocyte-vascular unit functions as a spatially organized pH-sensing system. We discuss how astrocytes simultaneously buffer extracellular pH and express ASICs, placing them at the center of a bidirectional metabolic feedback loop, and how ASICs in cerebrovascular cells may link neural metabolic load to vascular tone. Finally, we identify key open questions, including the spatial scale of physiologically relevant pH nano-domains, the role of ASIC tachyphylaxis as a "use-history" sensor, and whether ASIC-dependent metabolic signaling shapes circuit-level dynamics during sleep-wake transitions and high-demand cognitive states. This perspective reframes ASICs not merely as damage sensors but as constitutive physiological transducers of brain metabolic activity.

Mucociliary transport (MCT) is the dominant mechanical host defense system in human airways. Although the importance of the peripheral airway in the pathophysiology of bronchial asthma has recently attracted attention, the characteristics of MCT in the peripheral airway during asthma remain unclear. This study aimed to investigate MCT velocity in the central and peripheral airways and the effects of thymic stromal lymphopoietin (TSLP) on MCT. Central and peripheral airways were isolated from freshly obtained porcine airways immediately after slaughter. The airway specimens were mounted in a custom-built fluorescence microscopy-based measurement system. MCT velocity and ciliary beat frequency (CBF) were measured under the following conditions: without stimulation, in the presence of a low concentration of acetylcholine (ACh), and after stimulation TSLP, which reflects the pathophysiological condition of bronchial asthma. MCT velocity in the peripheral airways was slower than that in the central airways at less than one tenth (median: 75.40 μm/sec vs. 2.63 μm/sec). Under physiologically low ACh concentrations, MCT velocity was increased in the peripheral airway but not in the central airway. TSLP addition partially inhibited MCT velocity in both the central and peripheral airways by approximately two-thirds to one-half. TSLP also partially inhibited the CBF in both the central and peripheral airways from approximately two-thirds to one-third. Furthermore, TSLP receptor (TSLPR) expression was confirmed in airway tissues by immunohistochemical staining. The inhibitory effects of TSLP on MCT velocity were completely abolished by pre-incubation with a Janus kinase (JAK) inhibitor. In conclusion, TSLP has the potential to reduce MCT velocity, especially in the peripheral airways, by inhibiting TSLPR signaling pathways, resulting in impaired CBF. The characteristics of MCT differ between the central and peripheral airways. Importantly, TSLP-induced MCT impairment may aggravate mucus plug formation in the peripheral airways in patients with bronchial asthma.

Pancreatic α-cells play a key role in glucose homeostasis through glucagon secretion. Here, we discover that the bile acid-sensitive ion channel (BASIC), a Na[+] channel of the DEG/ENaC family, has a hitherto unrecognized role in α-cell function. We found that BASIC is mainly expressed in glucagon-positive α-cells of mouse islets. Genetic ablation of BASIC in mice reduced α-cell number, glucagon expression, and glucagon serum levels. These dramatic changes were accompanied by disturbed expression of α-cell specific transcription factors. Our findings identify BASIC as a previously unknown regulator of α-cell physiology.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by chronic hyperglycemia and represents a growing global health burden. One of its major complications is diabetic kidney disease (DKD), a progressive condition characterized by declining kidney function accompanied by structural alterations in tissue. Among the multiple pathways involved in DKD progression, inflammation has emerged as a key contributor. In parallel, increasing evidence suggests that biological sex influences disease progression; however, whether and how sex modulates inflammatory mechanisms driving DKD progression remains incompletely understood. In this study, we investigated the interplay between inflammation and biological sex in DKD using the BTBR ob/ob model, which closely recapitulates the human disease. Obese diabetic mice exhibited significant albuminuria regardless of sex; however, podocyte-associated proteins displayed sex-dependent molecular regulation. At the inflammatory level, no changes were detected in whole-kidney analyses based on the selected markers, but a compartment-specific response was observed, characterized by increased macrophage infiltration and upregulation of Ccl2 (MCP-1) gene expression in the glomerular compartment, especially in males. Additionally, the tubular compartment exhibited distinct sex- and metabolism-dependent inflammatory gene expression patterns. Together, these findings indicate that inflammation in this model is spatially compartmentalized and also differentially regulated according to sex. This integrated perspective may contribute to a better understanding of DKD progression and support the development of more precise and targeted therapeutic strategies.

The kidney slit diaphragm (SD) connects the foot processes of glomerular podocytes, anatomically forming the outermost part of the three-layered glomerular filtration barrier. The SD is a large molecular polymer that, together with the foot processes, covers the glomerular capillaries and has diverse functions. It establishes a strong yet flexible cell-cell contact between foot processes from neighboring podocytes and additionally acts as a dynamic signaling platform linking structural integrity with cellular responses. Understanding the physiology of the SD has been hampered by limited structural insights and a lack of precise knowledge of protein composition of its building blocks.The recent convergence of the proteomic analyses of the SD with atomically resolved structures and in situ cryo-electron tomography imaging have led to the fishnet SD. The fishnet SD is based on the high-resolution 3D cryo-electron tomographic images of native glomeruli that revealed an unexpected fishnet architecture, observed in mouse, fly and human. This breakthrough has provided a new and markedly different view of how we understand and analyze the SD. It provides important principles for understanding spatial self-organization, assembly, turnover, and force compensation and offers an important basis for functional investigations, including the elucidation of molecular mechanisms of clinically relevant diseases.

α-Klotho (hereafter Klotho) was discovered as an aging-suppressor protein whose function is intrinsically dependent on the kidney. Its shed ectodomain, soluble Klotho (sKlotho), is detectable in blood and urine. As an obligate co-receptor for endocrine fibroblast growth factor 23, Klotho operates at the intersection of mineral metabolism and chronic kidney disease (CKD). Within the kidney, Klotho expression is moderate in the proximal tubule but strongly enriched in the distal nephron, although the functional significance of this heterogeneity remains unclear. Recent findings from nephron segment-specific Klotho knockout mice reveal functional specialization of tubular Klotho along the nephron. According to the revised model, distal nephron Klotho regulates calcium reabsorption, bone remodeling, and urinary sKlotho levels. By contrast, proximal tubular Klotho regulates phosphate and vitamin D metabolism and is likely the principal source of circulating sKlotho; its loss recapitulates hyperphosphatemia, FGF23 resistance, and ageing-like phenotypes. This review re-evaluates the long-standing paradigm of renal Klotho biology in light of emerging evidence for functionally distinct proximal and distal nephron Klotho. Together, these insights place the kidney and its tubular Klotho heterogeneity at the center of mineral metabolism, aging and CKD.

Neuropeptide S (NPS) signaling is critically involved in arousal, sleep-wake regulation, fear and anxiety, and related forms of learning and memory, yet comparatively little is known about whether intrinsic properties of identified NPS neurons differ between sexes or fluctuate across the female estrous cycle. Here, we performed whole-cell patch-clamp recordings from genetically identified NPS-eGFP neurons in acute horizontal brainstem slices containing the peri-locus coeruleus (periLC) region. We show that periLC NPS neurons can be subdivided into two electrophysiologically distinct classes based on their discharge patterns from hyperpolarized membrane potentials: a delayed-onset firing phenotype (type I) and a regular-spiking phenotype (type II). Pharmacological and voltage-clamp analyses indicate that differential contribution of a transient A-type potassium current (IA), consistent with Kv4 channel function, is a key determinant of these firing phenotypes and provides a mechanism for gain control in type I neurons. Across male and female mice, we did not detect robust sex differences in the relative abundance of these neuronal classes or in overall excitability measures, suggesting that baseline intrinsic properties of periLC NPS neurons are broadly comparable between sexes. In contrast, estrous staging revealed a selective modulation of intrinsic discharge in females: during non-receptive stages (metestrus/diestrus), type I neurons exhibited higher spike output and increased instantaneous firing frequencies compared with receptive stages (proestrus/estrus), whereas type II neurons were comparatively stable across the cycle. These findings provide a cellular mechanism by which ovarian state may tune NPS neuron output and, consequently, the impact of NPS signaling on downstream circuits controlling arousal and stress-related behaviors.

Acid-sensing ion channels (ASICs) are proton-gated members of the degenerin/epithelial sodium channel family that are emerging as multifaceted regulators of cardiovascular function. ASICs expressed in baroreceptor, cardiac, and skeletal muscle afferents contribute to reflex control of blood pressure, cardiac function, and sympathetic outflow. In vascular smooth muscle and endothelial cells, ASICs integrate mechanical, metabolic, and humoral signals to regulate vascular tone. In the systemic circulation, ASIC2 contributes to pressure-dependent vasoconstriction of renal and cerebral arteries, supporting blood flow autoregulation and protection against organ injury. In contrast, ASIC1a promotes vasodilation, contributing to nitric oxide-dependent dilation in the cerebral arteries and to endothelium-dependent hyperpolarization and vasodilation in mesenteric arteries. In the pulmonary vascular smooth muscle cells, ASIC1a plays a central role in acute hypoxic- and receptor-mediated vasoconstriction, a role that becomes increasingly important in chronic hypoxia-induced pulmonary hypertension. Under these conditions, metabolic reprogramming drives extracellular acidification and enhances ASIC1a trafficking to the plasma membrane, promoting sustained depolarization, augmented store-operated calcium entry, and a hyperproliferative, apoptosis-resistant smooth muscle phenotype. ASIC1a additionally regulates mitochondrial homeostasis by modulating mitochondrial membrane potential, redox balance, and apoptotic susceptibility. Chronic hypoxia redistributes ASIC1a from mitochondria to the plasma membrane, leading to mitochondrial dysfunction and cell survival signaling, key features of pulmonary vascular disease. This review summarizes current understanding of ASIC function in the systemic and pulmonary vasculature and highlights non-proton-mediated signaling mechanisms, emerging mitochondria-specific mechanisms, sex-related differences, and therapeutic opportunities and challenges in targeting ASIC-dependent signaling pathways in vascular disease.

The physiology of neurons and synapses determines how networks in the brain process information. While these properties are well described in rodents, they are less well established for the human brain. Increasing availability of surgically resected human brain tissue, together with advances in electrophysiology, has enabled new insights into species-specific differences of the human cortical microcircuit. This review highlights recent progress in the physiology of layer 2 and 3 pyramidal neurons of the human temporal cortex, focusing on the multi-neuron patch-clamp approach. Methodological developments such as automated pipette cleaning now allow large-scale mapping of cellular electrophysiology and synaptic connectivity in human cortex. This approach reveals substantial functional heterogeneity among layer 2 and 3 pyramidal neurons with distinct intrinsic properties, morphology, and connectivity patterns. Complex network analyses further uncover human-specific properties, such as a directed network topology with random reciprocity and a decoupling of synaptic strength from connectivity. Network simulations suggest that these wiring patterns expand the computational capacity of cortical microcircuits. Together, these studies showcase the potential of multipatch recordings to bridge rodent and human neurophysiology and to establish an empirical basis for how cellular and synaptic diversity shapes human cortical microcircuits.

This conceptual review provides a synthesising narrative of the interdependent regulation of intracellular pH (pHi), nitric oxide (NO), and adenosine-the pHi-NO-adenosine triad-in fetoplacental endothelial dysfunction associated with gestational diabetes mellitus (GDM). GDM is associated with fetoplacental endothelial dysfunction, involving altered nitric oxide (NO) synthesis, reduced adenosine uptake, and dysregulated intracellular pH (pHi). Human umbilical vein endothelial cells (HUVECs) from GDM pregnancies exhibit increased endothelial NO synthase activity and decreased adenosine transport via human equilibrative nucleoside transporters, processes modulated by NO and pHi. These changes converge in the ALANO (Adenosine/L-Arginine/Nitric Oxide) signalling pathway, which enhances NO synthesis through increased L-arginine uptake. Importantly, similar mechanisms are observed in both macrovascular and microvascular endothelial cells, suggesting widespread placental vascular involvement. Maternal pre-pregnancy body mass index stratification reveals further heterogeneity in these responses. Disruptions in this signalling triad, i.e. NO, adenosine, and pHi, may impair placental perfusion, nutrient delivery, and fetal development, with potential long-term cardiometabolic consequences. Understanding these interrelated mechanisms provides a framework for targeted interventions in GDM, emphasizing the need for personalized approaches in maternal-foetal medicine.

Aluminum (Al[3+]) is a widespread environmental metal with potential effects on the intestinal epithelium. In this study, we evaluated the impact of dietary concentrations of aluminum on barrier integrity, histological organization, and gene expression in a 3D human intestinal tissue model. Tissues were exposed to increasing concentrations of aluminum (0, 5, 20, and 50 ppm) for 12 days to mimic environmental chronic exposure through ingestion. Transepithelial electrical resistance (TEER) measurements revealed a significant decrease only at the highest dose (50 ppm) on day 12, indicating a damage to the epithelial permeability. This was supported by a marked downregulation of OCLN and CLDN-5 expression, key genes involved in tight junction integrity. Aluminum permeation across the tissue was confirmed via Inductively Coupled Plasma-Atomic Emission Spectroscopy (ICP-AES), indicating dose-dependent penetration. Furthermore, gene expression analysis showed significant upregulation of MT-1E and MT-2 A (markers of cellular response to metal exposure) while MT-1 A remained unchanged. The present data demonstrate that repeated exposure to 50 ppm of Al3+ impacts intestinal barrier function and alters the tissue organization in the human intestinal epithelium.