Function (Oxford, England)最新文献

Sexual dimorphism profoundly influences physiology, disease susceptibility, and therapeutic responses, yet its effects on kidney mitochondrial function remain unclear. We hypothesized that sex differences in kidney mitochondrial function would parallel those in other organs, with females exhibiting greater oxidative capacity and lower oxidative stress. To test this, we measured oxidative phosphorylation (OXPHOS) kinetics and hydrogen peroxide (H2O2) emission in cortical and outer medullary (OM) mitochondria isolated from young male and female Dahl salt-sensitive (SS) rats maintained on a low-salt diet. Unexpectedly, male cortical mitochondria showed significantly higher O2 consumption during ATP synthesis (OXPHOS) than females when fueled by either complex I- or complex II-linked substrates. Cortical H2O2 emission was also greater in males, under both forward and reverse electron transport fueled by succinate. This was accompanied by increased Complex IV protein abundance without changes in mitochondrial DNA copy number or dynamics markers. In the OM, both mitochondrial respiration and H2O2 emission exceeded cortical levels, but showed no sex differences. Analysis of kidney transporter protein abundance revealed a sex-specific "downstream shift" in nephron transport, with males exhibiting greater proximal tubule (PT) sodium reabsorption potential and reduced distal transport capacity. Elevated cortical OXPHOS activity in males likely supports these higher PT energy demands. Thus, sex differences in renal mitochondrial function diverge from other organs, reflecting kidney-specific energetic priorities that override systemic maternal inheritance and sex hormone influences. Enhanced cortical H2O2 emission in males may underlie their heightened susceptibility to kidney injury and salt sensitivity.

Chronic pain is a multifactorial condition often accompanied by comorbidities such as anxiety, depression, and cardiovascular dysfunction. Traditional injury-based models have provided valuable mechanistic insights but are limited in their ability to capture the spontaneous, polygenic, and systemic nature of human chronic pain. Inherited pain models, such as consomic rat strains, transgenic mice, and recombinant inbred panels, offer a unique advantage towards bridging this translational gap: they enable the study of pain-related mechanisms in the absence of experimental injury, reducing confounding effects and better reflecting clinical complexity. These models serve as powerful platforms to investigate neuroimmune signaling, oxidative stress, and epigenetic regulation, and to explore how these pathways interact with sex, stress, and systemic comorbidities. Importantly, while referred to as "inherited pain models," these systems are not designed to model pain transmission across generations, but rather to uncover genetically driven susceptibility to pain and its mechanistic basis. Many of the mechanisms identified in these models overlap with findings from human genome-wide association studies, reinforcing their translational relevance. Beyond mechanistic discovery, inherited pain models can be used for the identification of biomarkers, the study of gene-environment interactions, and the development of mechanism-based therapies. Integration with multi-omics technologies and patient-derived systems further enhance their utility. This review highlights how these models are reshaping the field by enabling biologically informed approaches to diagnosis, prevention, and treatment, thus laying the foundations for a more precise and proactive era in pain medicine.

Randomization is a key component to scientific inquiry as it facilitates unbiased estimation of treatment effects via balancing of measured and unmeasured prognostic variables across treatment groups. Recent reports have noted that randomization is lacking in animal studies, threatening internal validity. Animal studies often involve rodents (mice or rats) sent in small batches to laboratories or bred on site in litters. Randomizing half of each batch to treatment and half to control (simple randomization) is a viable strategy to implementing randomization in animal studies, however experimenters may be concerned about chance imbalances, given the smaller sample sizes utilized in animal studies, in key prognostic variables, eg, baseline weight. Constrained randomization, wherein key prognostic factors are balanced within each batch, may offer benefits over simple randomization, especially if it were sequential, ie, could take balance of previous batches into account when randomly assigning treatment in current batch. Adjusting for prognostic variables in a statistical model is a way to address imbalances, independent of choice of randomization scheme. In simulations designed to mimic realistic scenarios, all methods of randomization tested led to unbiased treatment effect estimation, with model adjustment reducing standard errors and improving statistical power in all scenarios. Treatment effects in unadjusted and adjusted models were nearly an order of magnitude closer to each other in sequentially constrained randomization compared to simple randomization, yielding more robust findings.

Venous diseases commonly involve venous wall and/or valve dysfunction. Chronic venous dilation, a characteristic of varicose veins, can progress to the point where venous valve (VV) leaflets are pulled sufficiently apart that they no longer prevent back flow. Incompetent VVs increase the load on more distal valves by increasing the standing column of proximal blood. We tested VV function by isolating single valves from cervical veins of the mouse and measuring back leak and the adverse pressure gradient required for closure. Valve identification was facilitated by genetically forced expression of GFP in VV endothelium. A causal relationship was found between the relative diameter of the vein and VV closure, with a striking effect of venous tone: ∼60% of mature VVs in the cervical vein were incapable of closing if the vessel lost spontaneous tone and, in another ∼20% of veins, VVs closed only when venous tone exceeded some threshold value. Our results have important implications for the causes and possible treatment of VV incompetence in pathological states such as venous varicosity and chronic venous insufficiency. Moreover, they suggest an underappreciated mechanism whereby loss of venous tone can initiate a feed-forward cycle of events that make valve closure increasingly difficult, thereby elevating local venous pressure and exacerbating the loss of tone. This detrimental cycle may potentially be interrupted by appropriate pharmacological therapy to enhance venous tone and thereby restore VV competence.

Highly K+-selective potassium channels are essential for electrical signaling. The high selectivity of most K+ channels, with relative K+: Na+ permeabilities being as high as 100-1000:1 arises from the conserved so-called K+ channel selectivity filter (SF). Structural and computational studies have shown how the SF forms multiple sites that coordinate K+, by mimicking the water dipoles that coordinate K+ ions in solution, and thermodynamically favoring the binding of K+ over Na+. Selective conduction of K+ ions then results from a "knock-on" mechanism, whereby entering ions destabilize the next ion in the file. This review highlights key biophysical and biochemical research that provides insights to the atomic details of these processes. It then discusses how mutations that alter K+ selectivity and permeation in different K+ channels underlie multiple simple and complex diseases, illustrating how selectivity and permeation are central to physiology and to pathophysiology and important for physiologists to be aware of.

Metabolic dysfunction-associated steatotic liver disease and alcohol-associated liver disease frequently co-occur, manifesting as MetALD. Understanding the hepatocyte-specific effects of alcohol and metabolic stressors is critical to uncovering mechanisms of synergistic injury. This study evaluated the individual and combined effects of ethanol, sugars, and saturated/monounsaturated fats on hepatocyte lipid metabolism, oxidative stress, and mitochondrial function using a 3D human HepaRG spheroid model. HepaRG spheroids were treated with ethanol (50 mm), sugar (glucose and fructose), and fatty acids alone or in combination for 10 d. The combination of ethanol (E) and metabolic (sugar and fat, SF) stressors (ESF) synergistically increased triglyceride content and lipid droplet accumulation. ESF increased gene expression of lipid handling targets including perilipins 1 and 2, fatty acid binding protein 1, and hepatic lipase compared to controls. ESF also induced the highest rate of ROS production compared to E and SF and dysregulated antioxidant gene expression. E and SF additively impaired ATP content and ATP production linked mitochondrial respiration. Ethanol and metabolic stressors synergize to dysregulate hepatocyte lipid homeostasis and oxidative stress while additively impairing mitochondrial bioenergetics. Gene expression results suggest that lipid accumulation may be driven by altered expression of triglyceride storage and lipid handling markers rather than de novo lipogenesis. These findings highlight the importance of metabolic contributions in alcohol-induced hepatocellular dysfunction and establish HepaRG spheroids as a robust model to elucidate hepatocyte-specific responses in MetALD.

The consensus or canonical model of glucose-stimulated insulin secretion provides that the metabolism of glucose closes KATP channels by increase of the ATP/ADP ratio and that the ensuing depolarization-induced Ca2+ influx through voltage-dependent Ca2+ channels represents the immediate signal for the onset of exocytosis. However, it has been shown earlier that the depolarization-induced secretion can be suppressed by inhibition of the oxidative phosphorylation, pointing to an energy-requiring step presumably located downstream of Ca2+ influx. Here, we have investigated the relation between oxidative phosphorylation and the insulinotropic effect of K+ depolarization to better localize the energy-requiring step. The specific inhibitor of the mitochondrial F1FO ATPase, oligomycin, concentration-dependently and time-dependently inhibited the insulin secretion elicited by a strong K+ depolarization (40 mm). Perifusion with 4 µg/mL of oligomycin for 20, 10, or 5 min prior to the K+ depolarization reduced the amount of insulin secreted from freshly isolated islets from control value to about 5% with a half-time of 1.6 min. 0.4 µg/mL of oligomycin required more time for comparable effects. Cultured islets were less susceptible to the inhibitory action of oligomycin than fresh islets, corresponding to their significantly higher ATP/ADP ratio. The perifusion with oligomycin prior to the K+ depolarization did not decrease the depolarization-elevated cytosolic Ca2+ concentration and did not affect the resting plasma membrane potential and the extent of depolarization by 40 mm KCl. In conclusion, the exocytotic machinery of the beta cell requires a continuously running oxidative phosphorylation to remain responsive to the Ca2+ signal for granule fusion.

Chronic psychological stress has been linked to renal disease and is also associated with the development of hypertension. However, the mechanisms by which chronic stress alters renal function and promotes hypertension is unclear. This study tested the hypothesis that chronic stress causes impaired renal mitochondrial function that can lead to increased arterial pressure. Adult male and female C57BL/6 mice were exposed to a chronic unpredictable stress (CUS), or non-stress control, protocol for 28 consecutive days. The protocol models mild, persistent, and variable stress that is a common occurrence in daily life. The CUS protocol induced anxiety relevant behaviors in both male and female mice. CUS increased blood pressure in both sexes, but the increase was greater in female mice. Renal mitochondrial function was unchanged by CUS in male mice. In contrast, renal mitochondrial function was impaired in the proestrus phase of the estrous cycle in female mice. Female mice exposed to CUS had low renal progesterone. Impaired mitochondrial function correlated with low renal progesterone, which correlated with increased blood pressure. Renal sex steroids were unchanged by CUS in males. Urinary albumin excretion was significantly increased in female mice exposed to CUS. CUS did not affect urinary albumin excretion in male mice exposed to CUS. These data show a direct role for CUS in causing an increase in blood pressure. The mechanisms causing increased pressure in CUS-exposed mice are sex-dependent, with low renal progesterone leading to impaired renal mitochondrial function as a potential mechanism underlying the elevated pressure in female mice.

This review emphasizes the importance of investigating the gut itself-beyond microbiota-centered studies in the context of hypertension. Since the initial discovery of the connection between gut microbiota and blood pressure regulation, research has increasingly focused on understanding the role of gut microbiota and exploring strategies to modify it for better blood pressure management. The intestine as an organ has received comparatively less attention. Yet, hypertension-associated intestinal pathological changes are well documented in both rodent models and human patients. Research to restore the intestinal function may serve as a valuable but unexplored therapeutic target. This underscores the need for a summary of our understanding of the gut's intrinsic physiological and pathological roles in hypertension. To address this, we structured our review to (1) revisit the physiological functions of the intestine; (2) describe the pathological changes that are associated with hypertension; (3) summarize available current studies targeting to restore intestinal function for blood pressure control; and (4) discuss knowledge gaps and future opportunities.