BACKGROUND: An acidic lysosomal lumen (pH ~4.5) is essential for the degradative and signaling functions of this organelle, which serves as a central hub for cellular homeostasis. Lysosome pH (pHlys), however, is not sta...BACKGROUND: An acidic lysosomal lumen (pH ~4.5) is essential for the degradative and signaling functions of this organelle, which serves as a central hub for cellular homeostasis. Lysosome pH (pHlys), however, is not static but dynamically regulated by the coordinated action of the V-ATPase, counterion fluxes, membrane composition, and nutrient-sensitive signaling networks. PURPOSE: This review integrates recent advances in the molecular mechanisms regulating pHlys with emerging insights on how dysregulated pHlys contributes to pathologies in neurodegenerative disorders, lysosomal storage diseases, and cancers with changes in lumenal proteolytic activity and macromolecular degradation. MAIN FINDINGS: We discuss how pHlys acts as both a sensor and effector in lysosome biology, shaping transcriptional responses, membrane trafficking, and stress adaptation. We also review tools to measure pHlys, ranging from fluorescent dyes to genetically encoded biosensors and nanomaterial-based probes, and evaluate their use in disease-modeling applications. CONCLUSIONS: By highlighting pHlys as a nodal point in cellular functions, this review underscores the relevance of pHlys as a diagnostic marker and therapeutic target. Restoring pHlys in diseases offers translational potential to re-establish proteostasis and limit associated pathologies.
Jiménez-Sánchez L, Ruiz-López P, González-García P
… +10 more, Purhonen J, Martínez-Gálvez JM, López-Herrador S, Corral-Sarasa J, Díaz-Casado ME, Venegas C, Santos-Pérez I, Olivieri E, Rojas AL, López LC
Acta Physiol (Oxf)
· 2026 Mar · PMID 41702863
·
Full text
AIM: Mitochondrial dysfunction plays a central role in multiple neurodegenerative diseases, yet the temporal sequence of cellular events underlying neurodegeneration remains poorly defined. This study aimed to characteri...AIM: Mitochondrial dysfunction plays a central role in multiple neurodegenerative diseases, yet the temporal sequence of cellular events underlying neurodegeneration remains poorly defined. This study aimed to characterize the progression of neurodegeneration in a mouse model of fatal mitochondrial encephalopathy and to evaluate the therapeutic potential of oral N-acetylglucosamine supplementation. METHODS: A mouse model of primary coenzyme Q deficiency was used to examine neurodegeneration at presymptomatic, symptomatic and terminal stages. Neuronal integrity, glial activation, myelination and inflammatory responses were assessed using histological, molecular and ultrastructural approaches, together with behavioral analysis of motor coordination. N acetylglucosamine was administered orally from 1 month of age, and its effects on neuroinflammation, myelin integrity and motor performance were evaluated. RESULTS: Astrocyte activation and neuronal loss were detected before the onset of clinical symptoms, whereas proinflammatory microglia appeared at later disease stages. Early myelin abnormalities were accompanied by an initial increase in oligodendrocyte precursor cells, suggesting a compensatory response to early myelin stress. Oral N-acetylglucosamine supplementation reduced glial activation and neuroinflammatory markers, likely through modulation of inflammatory signaling pathways. Although treatment did not fully reverse structural damage or restore myelin protein expression, it led to a significant improvement in motor coordination. CONCLUSION: These findings define a temporal sequence of early glial activation, neuronal loss, and myelin alterations in mitochondrial encephalopathy. Targeting glial responses and neuroinflammation at early disease stages may mitigate neurodegenerative progression and improve functional outcomes, highlighting a physiologically relevant therapeutic window for mitochondrial disorders.
Acta Physiol (Oxf)
· 2026 Mar · PMID 41693628
·
Full text
AIM: Controversy exists on which metabolites determine the exaggerated exercise pressor reflex (EPR) in peripheral artery disease (PAD). In decerebrated rats, we investigated the role played by lactate and hydrogen ions...AIM: Controversy exists on which metabolites determine the exaggerated exercise pressor reflex (EPR) in peripheral artery disease (PAD). In decerebrated rats, we investigated the role played by lactate and hydrogen ions in a model of PAD, which was simulated by ligating the femoral artery for 72 h before the start of the experiment. METHODS: Production of lactate and hydrogen ions by the contracting hindlimb muscles was manipulated by knocking out the myophosphorylase gene (pygm). In both knockout (pygm; n = 13; 6-females) and wild-type rats (pygm; n = 14; 7-females), the EPR was evoked by statically contracting the triceps-surae muscles. Blood pressure, tension, and renal sympathetic nerve activity were measured. Responsiveness of the metabolic component of the EPR was evaluated by intra-arterial injections of lactic acid and diprotonated phosphate solutions. Responsiveness of the mechanical component of the EPR was evaluated by stretching the calcaneal tendon. In each rat, the pressor responses evoked from the freely perfused triceps-surae muscles were compared to those evoked from the contralateral ischemic triceps-surae muscles. RESULTS: In pygm rats whose femoral artery was ligated, static contraction, lactic-acid injection and diprotonated phosphate injection evoked pressor responses that were 88%, 22%, and 58% greater than those evoked from muscles whose femoral arteries were freely perfused. In pygm rats, ligation of the femoral artery for 72 h had no effect. In both groups, 72 h of femoral artery ligation exacerbated the pressor response to passive stretch. CONCLUSION: Lactate and hydrogen-ions accumulation in contracting myocytes plays a key role in exaggerating the metabolic component of the EPR evoked from hindlimb muscles with chronically-ligated femoral arteries.
Jaykumar AB, Monu SR, Xu J
… +4 more, Mendez M, Yang XP, Rhaleb NE, Ortiz PA
Acta Physiol (Oxf)
· 2026 Mar · PMID 41691606
·
Full text
UNLABELLED: Alström syndrome 1 (ALMS1) is a protein linked to Alström syndrome, a rare genetic disorder characterized by obesity, insulin resistance, hyperinsulinemia, and hypertension. Genetic studies have further assoc...UNLABELLED: Alström syndrome 1 (ALMS1) is a protein linked to Alström syndrome, a rare genetic disorder characterized by obesity, insulin resistance, hyperinsulinemia, and hypertension. Genetic studies have further associated Alms1 with hypertension in human populations. However, the precise mechanisms by which ALMS1 regulates metabolic and cardiovascular function remain unclear. AIM: In this study, we investigate metabolic and cardiovascular functions regulated by ALMS1. METHODS: To investigate this, we developed and characterized an Alms1 knockout (KO) rat model, which spontaneously develops metabolic syndrome and hypertension. RESULTS: Our findings reveal that Alms1 KO rats exhibit age-dependent metabolic dysfunction, with hypertension and increased body weight becoming evident by 10-12 weeks of age. Obesity, hyperinsulinemia, and vascular dysfunction emerge later, at 14-16 weeks, suggesting progressive metabolic deterioration. Notably, Alms1 KO rats develop hyperleptinemia as early as 7 weeks, prior to the onset of obesity, implicating ALMS1 in early leptin regulation and metabolic signaling. Moreover, female Alms1 KO rats develop severe metabolic syndrome with hypertension, like males, demonstrating a lack of the typical female cardiovascular protection. Echocardiographic analysis shows progressive cardiac dysfunction, including left ventricular (LV) dilation, increased wall thickness, and impaired contractility. Despite these structural changes, the LV mass/BW ratio remains unchanged, suggesting a shift toward maladaptive eccentric remodeling rather than hypertrophy. CONCLUSION: Collectively, these findings establish the Alms1 KO rat as a robust preclinical model of metabolic syndrome. This model closely mimics human disease and provides a powerful tool for studying the mechanisms of metabolic and cardiovascular dysfunction as well as for testing potential therapeutic interventions.
AIM: The current understanding of the underlying pathogenesis of depression is still limited. Silent information regulator 1 (SIRT1) has been shown to mediate the development of depression. However, the underlying mechan...AIM: The current understanding of the underlying pathogenesis of depression is still limited. Silent information regulator 1 (SIRT1) has been shown to mediate the development of depression. However, the underlying mechanisms are not well understood. METHODS: SIRT1 mice were used to observe the effect of selective knockdown of SIRT1 in glutamatergic or GABAergic neurons of the central amygdala (CeA) on depression-like behaviors. Western blot and immunofluorescence staining were used to determine the protein levels. Optogenetic technology was used to manipulate neuronal excitability. Whole cell patch-clamp recordings and c-Fos immunofluorescence staining were used to detect the excitability of different types of neurons. RESULTS: Our study demonstrated that selective knockdown of SIRT1 in CeA glutamatergic neurons induced depression-like behaviors and increased the excitability of glutamatergic neurons in mice. Optogenetic inhibition of glutamatergic neurons in CeA significantly ameliorated the depression-like behaviors induced by downregulation of SIRT1 in CeA glutamatergic neurons. In addition, selective knockdown of SIRT1 in CeA GABAergic neurons could also induce depression-like behaviors, accompanied by decreased excitability of GABAergic neurons and increased excitability of glutamatergic neurons. Optogenetic activation of GABAergic neurons in CeA significantly alleviated the depression-like behaviors induced by downregulation of SIRT1 in CeA GABAergic neurons. CONCLUSION: Our findings indicate that cell-type-specific loss of SIRT1 may mediate the development of depression-like behaviors in mice by divergent changes in the excitability of CeA glutamatergic and GABAergic neurons. These data demonstrate a new mechanism for the development of depression and provide a potential therapeutic target for depression.
Melica ME, Antonelli G, Peired AJ
… +1 more, Lasagni L
Acta Physiol (Oxf)
· 2026 Mar · PMID 41656065
·
Full text
AIM: The glomerulus is a specialized microvascular unit that filters plasma through the coordinated function of podocytes and parietal epithelial cells (PECs). From this perspective, the glomerulus functions like a livin...AIM: The glomerulus is a specialized microvascular unit that filters plasma through the coordinated function of podocytes and parietal epithelial cells (PECs). From this perspective, the glomerulus functions like a living hydrogeological filtration system. This review aims to integrate mechanobiology and hydrogeology, reframing podocytes and PECs as active regulators in a pressure-driven network, with Piezo1 central to glomerular homeostasis, adaptation, and pathology. METHODS: This review integrates existing literature on glomerular biology, mechanosensitive signaling, and epithelial cell function, focusing on podocytes, PECs, and mechanosensitive structures such as the Piezo1 channel. RESULTS: Podocytes form interdigitating foot processes connected by the slit diaphragm, forming both a selective barrier against protein loss and a mechanosensory interface. Through mechanosensitive structures, such as the Piezo1 channel, podocytes detect variations in hydrostatic pressure and transduce these cues into intracellular signaling that regulates permeability and preserves structural integrity. Sustained mechanical stress, however, can compromise podocyte function and viability. PECs line Bowman capsule, forming an impermeable boundary surrounding the filtration core. Once considered passive, PECs exhibit dynamic properties: some retain progenitor-like potential, contributing to repair, whereas others promote fibrosis in disease conditions. In this analogy, blood flow replaces groundwater while the multilayered filtration barrier mirrors stratified geological formations. Podocytes function as biological piezometers-sensing pressure and modulating filtration-while PECs resemble aquicludes, defining impermeable boundaries that can constrain or reshape the system under mechanical or inflammatory challenges. CONCLUSION: By integrating mechanobiology and hydrogeology, this review reframes the glomerulus as a living, pressure-driven filtration system in which podocytes and PECs act as active regulators rather than passive structural elements, with Piezo1 playing a central role in glomerular homeostasis, adaptation, and pathology.
AIM: Ketosis may represent a therapeutic target for age-related impairments in skeletal muscle function. This study investigated acute effects of ketosis on metabolic economy, mitochondrial function, and contractile para...AIM: Ketosis may represent a therapeutic target for age-related impairments in skeletal muscle function. This study investigated acute effects of ketosis on metabolic economy, mitochondrial function, and contractile parameters in skeletal muscle of young and older adults. METHODS: Twelve young (20-25 years) and twelve older (65-85 years) healthy men, matched by age-adjusted V̇Omax, participated in a randomized, crossover, double-blind intervention with ingestion of ketone monoester or placebo on separate study days. On both days, a low-dose, continuous glucose infusion blocked endogenous ketone production. Metabolic economy, oxidative capacity, muscle performance, intramuscular pH, and relative decline in peak power were assessed in the tibialis anterior through phosphorous MR spectroscopy (P-MRS) and dynamometer recordings. Mitochondrial function of the quadriceps femoris muscle was assessed by high-resolution respirometry. RESULTS: Ketosis had no effect on metabolic economy in either young or older participants. The older group showed lower metabolic economy compared to the young group. In older participants, ketones increased ATP production and time-torque derived work capacity. Oxidative capacity was similar between groups and remained unaffected by ketones. In the older group, ketones improved peak power and increased both muscle relative decline in peak power and contraction-induced pH decline. Complex I + II respiration was lower in older compared to young participants, with no effect of ketones. CONCLUSION: Ketosis enhanced skeletal muscle work capacity and ATP production in older but not young adults, suggesting an age-specific effect of ketone bodies on muscle function that operates independently of changes in metabolic economy and mitochondrial function. These findings support ketosis as a promising ergogenic therapy for older adults. TRIAL REGISTRATION: The study was pre-registered at clinicaltrials.gov (NCT05732909).
Auwerx H, Busch-Dohr M, Li X
… +2 more, Wagner CA, Bourgeois S
Acta Physiol (Oxf)
· 2026 Mar · PMID 41636123
·
Full text
AIM: Biallelic inactivating WDR72 variants are linked to distal renal tubular acidosis (dRTA), nephrocalcinosis, and amelogenesis imperfecta. The kidney shows high WDR72 expression; its precise localization and function...AIM: Biallelic inactivating WDR72 variants are linked to distal renal tubular acidosis (dRTA), nephrocalcinosis, and amelogenesis imperfecta. The kidney shows high WDR72 expression; its precise localization and function remain unclear. WDR72 is a member of the WD40 repeat domain protein family-a large group of scaffold proteins involved in various pathways, including vesicular trafficking-which has been suggested as a potential role for WDR72. This study investigates WDR72 expression and its role in renal acid-base homeostasis. METHODS: We analyzed WDR72/Wdr72 expression in single-cell transcriptome data from human and murine kidneys. We characterized Wdr72 female and male mice and assessed Wdr72 mRNA and protein localization, the ability of the kidney to excrete acid, and the expression and function of the H-ATPase. RESULTS: Transcriptome data showed that WDR72/Wdr72 is highly expressed in intercalated cells and other nephron segments. Immunohistochemistry localized WDR72 mostly at the apical membrane of type A-intercalated cells (A-IC). Wdr72 mice exhibited alkaline urine under normal conditions, but only female knockout mice developed a pronounced metabolic acidosis upon dietary acid loading. Western blot analyses revealed sex-dependent WDR72 expression changes with acid loading. Expression of several H-ATPase subunits was dysregulated in Wdr72 kidneys while their localization in intercalated cells remained intact. Lower expression of H-ATPase subunits was paralleled by reduced H-ATPase activity observed in isolated microperfused collecting ducts. CONCLUSION: These findings identify WDR72 as a critical regulator of type A-intercalated cell dependent urinary acidification, modulating H-ATPase activity. The sex-specific metabolic phenotype reveals a novel mechanism underlying sex differences in renal acid handling.
Volkert M, Dinh HA, Scholl UI
… +1 more, Stölting G
Acta Physiol (Oxf)
· 2026 Mar · PMID 41606697
·
Full text
AIM: The zona glomerulosa (ZG) of the adrenal cortex regulates blood pressure and electrolyte homeostasis through aldosterone production. In ZG cells, potassium and angiotensin II (Ang II) trigger calcium oscillations th...AIM: The zona glomerulosa (ZG) of the adrenal cortex regulates blood pressure and electrolyte homeostasis through aldosterone production. In ZG cells, potassium and angiotensin II (Ang II) trigger calcium oscillations that drive aldosterone synthesis. Changes in serum osmolality also modulate aldosterone production in a chloride-dependent fashion, but the involved proteins remain unclear. Because the chloride channel ClC-2 is activated by hypoosmolality, we investigated its role in ZG osmoregulation. METHODS: We used Clcn2 knockout (KO) and wild-type (WT) mice. Explanted adrenal glands were incubated with iso- and hypotonic solutions for measurements of aldosterone. Acute adrenal slices were studied using calcium and chloride sensitive fluorescent dyes. We also investigated ClC-2's systemic importance by inducing a hyponatremic hypoosmolality in mice using desmopressin. RESULTS: Under hypoosmolar conditions, WT adrenals upregulated aldosterone production in vitro, an effect that was absent in the KO. WT cells responded to hypoosmolality with increased intracellular calcium levels. This response was abrogated in KO cells. Intracellular chloride levels were higher in ZG cells from KO adrenal slices. This suggests that ClC-2 provides a hypoosmolality-dependent chloride efflux pathway that is missing in the KO. Systemic hypoosmolality in mice induced by desmopressin did not differentially affect blood aldosterone levels. CONCLUSION: ClC-2 plays a role in the ZG's response to reduced extracellular osmolality through chloride outflow, which likely causes depolarization, voltage-dependent calcium influx, and aldosterone production. These data advance our understanding of regulators of aldosterone production.
Wences Chirino T, Adammek F, Belen S
… +15 more, Winker M, Proschinger S, Rademacher A, Schlagheck ML, Schenk A, Kupjetz M, Walzik D, Warnke C, Reuter M, Rosenberger F, Meyer T, McCann A, Ueland PM, Joisten N, Zimmer P
Acta Physiol (Oxf)
· 2026 Mar · PMID 41606419
·
Full text
AIM: Indoles are tryptophan (Trp)-derived metabolites that are produced by the gut microbiota and may influence the gut-microbiota-brain axis in multiple sclerosis (MS). Indole-3-lactate (ILA) is reduced in persons with...AIM: Indoles are tryptophan (Trp)-derived metabolites that are produced by the gut microbiota and may influence the gut-microbiota-brain axis in multiple sclerosis (MS). Indole-3-lactate (ILA) is reduced in persons with MS and improves MS clinical scores in animal models via its anti-inflammatory remyelinating properties. The ILA/indole-3-acetate (IAA) (ILA/AA) index is considered a neuroprotection index. Physical exercise and diet can modify gut microbiota and indole metabolism. METHODS: This secondary analysis of a randomized control trial aimed to assess the effects of acute and chronic exercise on serum indoles in relapsing-remitting MS (RRMS). Thirty-one RRMS patients (≥ 70% session attendance) completed a 10 week multimodal functional training (60 min, 3×/week) vs. a waitlist control group. Blood samples were collected at baseline and compared to a matched healthy control group, and after 10 weeks for the assessment of chronic effects. Additionally, acute effects of a single bout of exercise were assessed with a blood sample before, during, and immediately after one interim training session. Serum indole concentrations were measured using LC-MS/MS. RESULTS: Baseline indole levels in RRMS patients differed from those of matched healthy controls, and reduced ILA levels were observed. The 10 week intervention increased the ILA/IAA index, while a single exercise bout induced an increase in both ILA and ILA/IAA. CONCLUSION: Multimodal functional training over 10 weeks led to an improved ILA/IAA index suggesting a neuroprotective shift in gut microbiota composition, and a single bout acutely increases the circulating level of ILA. STUDY REGISTRATION NUMBER: DRKS00017091.
AIM: The secondary motor cortex (M2) is engaged in behavioral planning, movement preparation, and the execution of complex motor sequences in a specific order. However, the nature of neuronal signals encoded by M2 neuron...AIM: The secondary motor cortex (M2) is engaged in behavioral planning, movement preparation, and the execution of complex motor sequences in a specific order. However, the nature of neuronal signals encoded by M2 neurons (i.e., reward or aversive) and their behavioral effects on motor sequence learning remain unclear. This study aimed to elucidate the nature of these signals and their regulatory roles in motor behavior. METHODS: We combined in vivo fiber photometry with optogenetics in mice undergoing conditioning paradigms and motor sequence learning tasks. Calcium signals were recorded from general M2 neurons, PV interneurons, and VgluT2 projection neurons in response to reward (sucrose) and aversive (foot-shock, LiCl) stimuli. Furthermore, M2 neurons were optogenetically activated during reward delivery in the motor sequence learning task. The behavioral outcomes were further dissected using progressive ratio and open-field tests to distinguish between motivational and direct motor effects. RESULTS: M2 neurons, including PV and VgluT2 subpopulations, consistently encoded aversive signals, exhibiting negative responses to rewards and positive responses to aversive stimuli. Crucially, optogenetic activation of M2 neurons during reward delivery significantly suppressed the initiation and execution of motor sequences. This behavioral impairment was driven by a reduction in motivational vigor, indicated by decreased lever pressing and a lower break point in the progressive ratio test. CONCLUSION: M2 neurons encode aversive signals that functionally devalue rewards, thereby reducing motivation and inhibiting motor sequence learning. These results identify M2 as a critical node in neural circuits that adaptively gates motor output based on negative motivational valence.
AIM: Control of synaptic inhibition at the network level is essential for neuronal computation; however, the mechanism by which inhibitory I → I synapses between interneurons adjust their strength remains unclear. Here,...AIM: Control of synaptic inhibition at the network level is essential for neuronal computation; however, the mechanism by which inhibitory I → I synapses between interneurons adjust their strength remains unclear. Here, we describe a non-Hebbian form of inhibitory long-term depression (iLTD) that operates at vasoactive intestinal peptide (VIP) interneuron inputs onto stratum oriens interneurons in the hippocampal CA1 region. METHODS: Whole-cell recordings of oriens interneurons combined with optogenetic VIP-positive input activation in mouse hippocampal slices. RESULTS: Repeated postsynaptic burst firing alone was sufficient to induce a persistent weakening of VIP-mediated I → I inhibitory transmission onto oriens interneurons. This plasticity was insensitive to presynaptic stimulation paired with postsynaptic burst spiking, confirming its non-Hebbian character. The observed iLTD required postsynaptic calcium influx through L- and T-type voltage-gated calcium channels but was independent of endocannabinoid signaling, indicating a postsynaptic mechanism. To better define the cell-specificity of plastic changes at I → I synapses on oriens interneurons, we compared these findings with plasticity induced by analogous protocols at inhibitory synapses formed by two major interneuron types (parvalbumin- and somatostatin-positive) onto pyramidal neurons. These synapses, however, followed classical and subtype-specific Hebbian spike-timing-dependent rules and were unaffected by postsynaptic burst activity. Notably, physiologically relevant theta-burst stimulation of excitatory inputs to oriens interneurons induced heterosynaptic I → I iLTD and increased the excitatory/inhibitory balance in these cells, thereby enhancing their recruitment. CONCLUSIONS: Our findings identify a cell-type-specific, activity-history-dependent rule of inhibitory I → I plasticity that weakens disinhibition in a non-Hebbian manner, revealing a novel physiological mechanism that modulates gain within hippocampal microcircuits.
Changes in muscle mass and force are mainly related to changes in fiber size. In eukaryotes, DNA-content and cell size are generally correlated, suggesting the existence of a DNA-template limitation. This might be partic...Changes in muscle mass and force are mainly related to changes in fiber size. In eukaryotes, DNA-content and cell size are generally correlated, suggesting the existence of a DNA-template limitation. This might be particularly important in the skeletal muscle fiber syncytia, which contain 30%-50% less DNA per cytoplasmic volume than most cells. Muscle fibers display a correlation between fiber size and myonuclear number, and genetically reducing the number reduces the size. Even so, the cytoplasmic volume per nucleus is larger in larger cells, demonstrating some flexibility in each nucleus' ability to "produce volume." De novo hypertrophy leads to accrual of myonuclei, which do not seem to be lost; the "extra" nuclei might serve as a mechanism for muscle memory. A complementary hypothesis is that muscle memory relies on each nucleus' ability to provide protein related to persistent/long-lasting epigenetic traces. A few epigenetically altered loci have been suggested, but there is currently no consensus between various studies as to which these are.
AIM: Renal fibrosis is a major contributor to chronic kidney disease (CKD) progression and eventual organ failure. G protein-coupled bile acid receptor 1 (TGR5) was previously shown to have beneficial effects on kidney d...AIM: Renal fibrosis is a major contributor to chronic kidney disease (CKD) progression and eventual organ failure. G protein-coupled bile acid receptor 1 (TGR5) was previously shown to have beneficial effects on kidney diseases. The current study aimed to investigate whether TGR5 activation prevents kidney fibrosis and to clarify the underlying mechanism. METHODS: TGR5 expression was examined in human fibrotic kidneys. Two animal models of renal fibrosis were used: unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion injury with contralateral nephrectomy (uIRIx) in wild-type and TGR5 knockout mice. Renal histology, extracellular matrix (ECM) deposition, and renal function were examined. In vitro studies were performed on human proximal tubular HK2 cells by treating them with transforming growth factor-β1 and TGR5 agonists/antagonists. RESULTS: TGR5 was significantly downregulated in fibrotic human kidneys. In both UUO and uIRIx models, TGR5 activation by lithocholic acid alleviated renal fibrosis, reduced ECM deposition, and improved kidney function. Conversely, Tgr5 knockout in mice exacerbated fibrotic injury. Mechanistically, TGR5 activation prevented fibrosis development, probably by enhancing NEDD4L-mediated ubiquitination and degradation of phosphorylated Smad2/3 by inhibiting the upstream PI3K-SGK1 pathway. CONCLUSION: TGR5 activation protects against renal fibrosis by inhibiting the PI3K-SGK1-NEDD4L axis and promoting p-Smad2/3 degradation.
Vilches-Herrando E, Rodríguez-Bey G, Hernández RG
… +5 more, Gento-Caro Á, Pastor ÁM, Campos-Caro A, González-Forero D, Moreno-López B
Acta Physiol (Oxf)
· 2026 Feb · PMID 41521833
·
Full text
AIM: Identifying interactors in sensorimotor processing and neurotransmission remains a current challenge for understanding neural information processing and brain function. METHODS: To evaluate the role of p11 in sensor...AIM: Identifying interactors in sensorimotor processing and neurotransmission remains a current challenge for understanding neural information processing and brain function. METHODS: To evaluate the role of p11 in sensorimotor processing and excitatory synaptic neurotransmission, neuron-specific lentivirus-directed p11 silencing, small interfering RNA (siRNA)-induced p11 deletion, unitary extracellular recordings of hypoglossal motor neurons (HMNs), western blot, co-immunoprecipitation, multiple immunolabeling, proximity ligation (PLA) assays, electron microscopy, and whole-cell patch-clamp recording of AMPA receptor-mediated excitatory postsynaptic currents in adult and/or neonatal rat HMNs were performed. RESULTS: p11 knockdown depressed baseline and chemoreceptor-modulated inspiratory-related activity in HMNs. Co-immunoprecipitation and PLA assays indicated that p11 interacts with Munc13-1, a presynaptic active zone (AZ) protein for vesicle priming, presumably at excitatory inputs in the hypoglossal nucleus. Interference with p11 resulted in Munc13-1 downregulation, reduction in AZ length, and increased vesicle accumulation at excitatory boutons on HMNs, without affecting the number of docked vesicles at the AZ. p11 knockdown robustly reduced the synaptic strength of excitatory neurotransmission incoming to HMNs by affecting both the synchronous and asynchronous phases of neurotransmitter release. The decrease in synaptic strength was concurrent with a reduction in the size of the "functional" pool of readily releasable (RRP) vesicles and with the slowing down of the vesicle recruitment rate to replenish RRP. CONCLUSION: p11 is proposed as a relevant mediator in the neurotransmitter release by regulating vesicle dynamics at central excitatory synapses. Here, p11 is highlighted as a multifaceted factor involved in neurotransmission and synaptic plasticity and, therefore, central for neural information processing.