Piezo Channels Research Articles

Mechanisms of mechanotransduction and physiological roles of PIEZO channels.

Mechanical force is an essential physical element that contributes to the formation and function of life. The discovery of the evolutionarily conserved PIEZO family, including PIEZO1 and PIEZO2 in mammals, as bona fide mechanically activated cation channels has transformed our understanding of how mechanical forces are sensed and transduced into biological activities. In this Review, I discuss recent structure-function studies that have illustrated how PIEZO1 and PIEZO2 adopt their unique structural design and curvature-based gating dynamics, enabling their function as dedicated mechanotransduction channels with high mechanosensitivity and selective cation conductivity. I also discuss our current understanding of the physiological and pathophysiological roles mediated by PIEZO channels, including PIEZO1-dependent regulation of development and functional homeostasis and PIEZO2-dominated mechanosensation of touch, tactile pain, proprioception and interoception of mechanical states of internal organs. Despite the remarkable progress in PIEZO research, this Review also highlights outstanding questions in the field.

LOX-mediated ECM mechanical stress induces Piezo1 activation in hypoxic-ischemic brain damage and identification of novel inhibitor of LOX

Hypoxic-ischemic encephalopathy (HIE) poses a significant challenge in neonatal medicine, often resulting in profound and lasting neurological deficits. Current therapeutic strategies for hypoxia-ischemia brain damage (HIBD) remain limited. Ferroptosis has been reported to play a crucial role in HIE and serves as a potential therapeutic target. However, the mechanisms underlying ferroptosis in HIBD remain largely unclear. In this study, we found that elevated lysyl oxidase (LOX) expression correlates closely with the severity of HIE, suggesting LOX as a potential biomarker for HIE. LOX expression levels and enzymatic activity were significantly increased in HI-induced neuronal models both in vitro and in vivo. Notably, we discovered that HI-induced brain tissue injury results in increased stiffness and observed a selective upregulation of the mechanosensitive ion channel Piezo1 in both brain tissue of HIBD and primary cortex neurons. Mechanistically, LOX increases its catalytic substrates, the Collagen I/III components, promoting extracellular matrix (ECM) remodeling and possibly mediating ECM cross-linking, which leads to increased stiffness at the site of injury and subsequent activation of the Piezo1 channel. Piezo1 senses these stiffness stimuli and then induces neuronal ferroptosis in a GPX4-dependent manner. Pharmacological inhibition of LOX or Piezo1 ameliorated brain neuronal ferroptosis and improved learning and memory impairments. Furthermore, we identified traumatic acid (TA) as a novel LOX inhibitor that effectively suppresses LOX enzymatic activity, mitigating neuronal ferroptosis and promoting synaptic plasticity. In conclusion, our findings elucidate a critical role for LOX-mediated ECM mechanical stress-induced Piezo1 activation in regulating ferroptotic cell death in HIBD. This mechanistic insight provides a basis for developing targeted therapies aimed at ameliorating neurological outcomes in neonates affected by HIBD.

PIEZO1 variants that reduce open channel probability are associated with familial osteoarthritis.

The synovial joints senses and responds to a multitude of physical forces to maintain joint homeostasis. Disruption of joint homeostasis results in development of osteoarthritis (OA), a disease characterized by loss of joint space, degeneration of articular cartilage, remodeling of bone and other joint tissues, low-grade inflammation, and pain. How changes in mechanosensing in the joint contribute to OA susceptibility remains elusive. PIEZO1 is a major mechanosensitive cation channel in the joint directly regulated by mechanical stimulus. To test whether altered PIEZO1 channel activity causes increased OA susceptibility, we determined whether variants affecting PIEZO1 are associated with dominant inheritance of age-associated familial OA. We identified four rare coding variants affecting PIEZO1 that are associated with familial hand OA. Single channel analyses demonstrated that all four PIEZO1 mutant channels act in a dominant-negative manner to reduce the open probability of the channel in response to pressure. Furthermore, we show that a GWAS mutation in PIEZO1 associated with reduced joint replacement results in increased channel activity when compared with WT and the mutants. Our data support the hypothesis that reduced PIEZO1 activity confers susceptibility to age-associated OA whereas increased PIEZO1 activity may be associated with reduced OA susceptibility.

Mechanosensing by Piezo1 regulates osteoclast differentiation via PP2A-Akt axis in periodontitis.

The mechanosensitive Ca 2+ channel Piezo1 plays important regulatory roles in a variety of cellular activities. RANKL-mediated OC-genesis requires permissive co-stimulatory signal from ITAM receptors, such as OSCAR and TREM2, to trigger the calcineurin/calmodulin signaling axis via Ca 2+ oscillation, thereby upregulating NFATc1 expression. Activation of Piezo1 remarkably suppressed RANKL-induced NFATc1 activation which, in turn, reduced OC-genesis. Such mechanical activation of Piezo1 expressed on pre-OCs induced intracellular Ca 2+ influx. Nonetheless, PP2A-mediated dephosphorylation of Akt, not the calcineurin/calmodulin pathway, suppressed NFATc1 in RANKL-elicited OC-genesis and resultant bone resorption, both in vitro and in vivo . These results indicate that mechanostress applied to pre-OCs can downregulate pathogenic OC-genesis and that Piezo1, as the mediator, is a novel molecular target for the development of anti-osteolytic therapies.

Activation of Piezo1 channels enhances spontaneous contractions of isolated human bladder strips via acetylcholine release from the mucosa

Enhanced spontaneous bladder contractions (SBCs) have been thought one of the important underlying mechanisms for detrusor overactivity (DO). Piezo1 channel has been demonstrated involved in bladder function and dysfunction in rodents. We aimed to investigate the modulating role of Piezo1 in SBCs activity of human bladder. Human bladder tissues were obtained from 24 organ donors. SBCs of isolated bladder strips were recorded in organ bath. Piezo1 expression was examined with reverse transcription-quantitative polymerase chain reaction and immunofluorescence staining. ATP and acetylcholine release in cultured human urothelial cells was measured. Piezo1 is abundantly expressed in the bladder mucosa. Activation of Piezo1 with its specific agonist Yoda1 (100 nM–100 μM) enhanced the SBCs activity in isolated human bladder strips in a concentration-dependent manner. The effect of Yoda1 mimicked the effect of a low concentration (30 nM) of carbachol, which can be attenuated by removing the mucosa, blocking muscarinic receptors with atropine (1 μM), and blocking purinergic receptors with pyridoxal-phosphate-6-azophenyl-2′,4′-disulfonate (PPADS, 30 μM), but not by tetrodotoxin (1 μM). Activation of urothelial Piezo1 with Yoda1 (30 μM) or hypotonic solution induced the release of ATP and acetylcholine in cultured human urothelial cells. In patients with benign prostatic hyperplasia, greater Piezo1 expression was observed in bladder mucosa from patients with DO than patients without DO. We conclude that upregulation and activation of Piezo1 may contribute to DO generation in patients with bladder outlet obstruction by promoting the urothelial release of ATP and acetylcholine. Inhibition of Piezo1 may be a novel therapeutic approach in the treatment of overactive bladder.

Mechanosensitive Piezo channels and their potential roles in peripheral auditory perception

AbstractHearing sound and responding to external and internal mechanical stimuli requires specific proteins as mechanotransducers that convert mechanical forces into biological signals. However, our understanding of the mechanotransduction process in the inner ear is still incomplete. Mechanically activated ion channels, PIEZO1 and PIEZO2, are widely distributed throughout the body and play essential roles. Recent studies have discovered that Piezo channels are expressed in inner ear hair cells, suggesting their potential involvement in auditory perception. This review summarizes the existing discoveries about the Piezo channels, including their structure, mechanogating mechanisms, and general physiological roles, explicitly focusing on Piezo channels in the auditory systems. Piezo channels play roles in ultrasound perception, generation of anomalous current, hair cell development, and potentially in the normal mechanoelectrical transduction process of hair cells. Collectively, this review aims to provide a new perspective on the Piezo channel and its potential roles in auditory perception.

Abstract P434: Piezo2 Channels in JG cells do not Regulate Renin Expression or Renin Release to the Circulation

Kidneys are central to blood pressure regulation through the renin-angiotensin system. Renin-producing juxtaglomerular (JG) cells act as renal baroreceptors by controlling renin release according to the changes in perfusion pressure. Recent studies suggest that Piezo2 calcium channels may regulate the baroreceptor mechanism of renin release. However, our single-cell RNAseq and RNAScope analysis on adult kidneys showed a very low expression for Piezo2 in the JG cells. Since it is unclear if Piezo2 in the JG cells regulates renin expression and release, we defined the in vivo role of Piezo2 in the current study using Piezo2 conditional mutant mice. For this we generated Piezo2 fl/fl ;Ren1 d Cre, Piezo2 fl/del ;Ren1 d Cre and Piezo2 fl/fl ;Akr1b7.Cre-Er T2 mice. Though we detected an efficient deletion of Piezo2 by RNAScope in the JG cells of the mutant kidneys, we did not observe a significant difference in the renin signals between the control and the mutant groups by renin immunostaining. q-RT-PCR of the kidney cortices to measure renin mRNA levels and renin-specific ELISA to quantify plasma renin levels also indicated no significant differences (NS) between the control and the mutant groups ( Piezo2 fl/fl ;Ren1 d Cre - Relative renin mRNA levels: Control (n=11) 1.05±0.113 Mutants (n=6) 0.90±0.20, NS; Plasma renin levels (pg/ml): Control (n=11) 17472±3712 Mutants (n=6) 14934±3547, NS; Piezo2 fl/del ;Ren1 d Cre - Relative renin mRNA levels: Control (n=3) 0.98±0.13 Mutants (n=4) 1.04±0.19, NS; Plasma renin levels (pg/ml): Control (n=3) 20221±4303 Mutants (n=4) 15014±1901, NS). Furthermore, subjecting the mice to hypotension and volume depletion with captopril and a low salt diet for one week did not affect the renin expression due to Piezo2 deletion in the renin cells. Finally, our results from the aortic coarctation surgery model showed that Piezo2 deletion in the adult JG cells of Piezo2 fl/fl ;Akr1b7.Cre-Er T2 mice did not affect the changes in renin expression between the left and right kidneys in response to perfusion pressure (Relative renin mRNA levels: Control (n=11) LK-1.102 ±0.173 RK-0.316±0.046, p=0.002 Mutants (n=9) LK-1.191±0.266 RK-0.524±0.212, p=0.05). Collectively, our in vivo data shows that renin expression is unaffected during normal conditions and when homeostasis is threatened by hypotension, sodium depletion, or changes in blood pressure, indicating that Piezo2 channels are not necessary for renin synthesis and release to circulation in JG cells.

Keratinocyte Piezo1 and CD39 initiated the acupuncture analgesic signals via Co-regulating extracellular ATP mobilization at acupoints

Acupoints are the initiation sites for acupuncture analgesic signals, where adenosine signaling plays a crucial role. A comprehensive understanding of this matter will guide clinicians to optimize acupuncture manipulations to improve acupuncture effectiveness. Recently, keratinocyte Piezo1 channels and cascade ATP release are independently unveiled to be essential for the skin tactile sensation. Thus, we aimed to investigate whether keratinocyte Piezo1-mediated ATP release, in orchestration with CD39, contributed to this initiation mechanism via producing adenosine. 20-min needling was administered at the unilateral ST36 acupoint on the acute ankle arthritis rats. The pain thresholds in the affected hindpaws were determined. Interstitial ATP and adenosine were extracted with microdialysis and assessed by luciferase-luciferin and HPLC, respectively. To simulate needling stimulation, keratinocyte HaCaT cells were subjected to hypotonic shock. ATP release and live calcium imaging were conducted. Immunofluorescence labeling showed the presence of Piezo1 and CD39 on keratinocytes. Acupuncture led to a prompt analgesic effect, as well as a temporary accumulation of ATP and adenosine. Activating adenosine A1 receptors, promoting ATP release by activating Piezo1, or facilitating ATP hydrolysis by potentiating CD39 achieved anti-nociceptive effects. Conversely, altering these modulations in the opposite direction reversed the subsequent effects of acupuncture. Needling-induced accumulation of interstitial ATP parallelly changed with these modulations. Hypotonic shock led to ATP release and [Ca2+]i rise in HaCaT, which were impeded by introducing siRNA-Piezo1, or replicated by agonism at Piezo1. These findings suggest that keratinocyte Piezo1 and CD39 co-mediated ATP mobilization at acupoints contributes to the initiation signals of acupuncture analgesia via triggering adenosine signaling. SectionPhysical/Mental practices (acupuncture) Taxonomy (classification by evise)pain and analgesia.

Abstract P221: Yoda2, a Novel Piezo1 Agonist, Induces Relaxation in Mouse Vascular and Corpus Cavernosum Tissues

Introduction: Piezo1, a mechanosensitive nonselective cation channel, is expressed in endothelial and vascular smooth muscle cells. It plays a critical role in sensing endothelial shear stress, generating nitric oxide (NO), regulating vascular tone, promoting angiogenesis, and controlling blood pressure. Yoda1, a tool compound for Piezo1, has limitations due to its low potency and poor water solubility. To overcome these limitations, a Yoda1 analogue, Yoda2, was developed. Yoda2 features a 4-benzoic acid moiety replacing the pyrazine of Yoda1, thereby enhancing its agonist properties and solubility. We hypothesize that Yoda2 induces relaxation in mouse mesenteric resistance artery (MRA), pudendal artery (PA), and corpus cavernosum (CC), through a NO-dependent mechanism. Methods: Male C57BL/6 mice were euthanized, and their MRA, PA, and CC were isolated and mounted in DMT wire myographs for isometric force measurements. Concentration-response curves to Yoda2 were obtained. Additionally, the contraction of CC induced by electrical field stimulation (EFS) was evaluated in the absence or presence of Yoda2. Data are presented as mean ± S.E.M of 3-4 mice. Non-linear regression curve was performed, and the maximum response (E max ) and pharmacological potency (pEC 50 ) were analyzed using Student's t-test (p<0.05). Results: Yoda2 induced concentration-dependent relaxation in the MRA, PA, and CC, with E max values of 98.31 ± 0.89% for MRA, 95.01 ± 3.75% for PA, and 75.03 ± 15.17% for CC. The role of NO in this pathway was confirmed by the attenuation of Yoda2 effects upon inhibition of NO synthase (NOS) with L-NAME in MRA and PA. Furthermore, Yoda2 (1 µM) decreased the concentration response curves for phenylephrine-induced contraction in PA and MRA. On the other hand, Yoda2 (30 µM) did not change the EFS-induced contraction in CC. Conclusion: This study is the first to demonstrate that Yoda2, a potent and water-soluble Piezo1 channel agonist, induces significant relaxation in the MRA, PA, and CC of mice. Consistent with the effects of Yoda1, the effects of Yoda2 are mediated through NO production.

David Julius and Ardem Patapoutian: Pioneers in Sensory Biology and Neuroscience.

Sensory biology is a critical area within neuroscience, exploring how organisms respond to environmental stimuli such as temperature, pain, and mechanical forces. David Julius and Ardem Patapoutian have made landmark contributions to this field by identifying crucial receptors. Julius's discovery of transient receptor potential (TRP) channels, including transient receptor potential cation channel subfamily V member 1 (TRPV1), which detects heat and pain, revolutionized sensory biology and opened new paths for pain management. Similarly, Patapoutian's identification of Piezo channels, which respond to mechanical stimuli like touch and pressure, has deepened our understanding of sensory perception. Their combined work has not only advanced scientific knowledge but also introduced potential treatments for chronic pain and sensory disorders. This paper reviews their contributions and the broader implications for sensory biology and therapeutic developments.

Resting human trabecular meshwork cells experience tonic cation influx.

The trabecular meshwork (TM) regulates intraocular pressure (IOP) by converting biochemical and biomechanical stimuli into intracellular signals. Recent electrophysiological studies demonstrated that this process is mediated by pressure sensing ion channels in the TM plasma membrane while the molecular and functional properties of channels that underpin ionic homeostasis in resting cells remain largely unknown. Here, we demonstrate that the TM resting potential is subserved by a powerful cationic conductance that disappears following Na+ removal and substitution with choline or NMDG+. Its insensitivity to TTX, verapamil, phenamil methanesulfonate and amiloride indicates it does not involve voltage-operated Na+, Ca2+ and epithelial Na+ (ENaC) channels or Na+/H+ exchange while a modest hyperpolarization induced by SEA-0440 indicates residual contribution from reversed Na+/Ca2+ exchange. Tonic cationic influx was inhibited by Gd3+ and Ruthenium Red but not GsMTx4, indicating involvement of TRP-like but not Piezo channels. Transcriptional analysis detected expression of most TRP genes, with the canonical transcriptome pool dominated by TRPC1 followed by the expression ofTRPV1, TRPC3 and TRPC5. TRPC3 antagonist Pyr3 and TRPC1,4,5 antagonist Pico1,4,5 did not affect the standing current, whereas the TRPC blocker SKF96365 promoted rather than suppressed, Na+ influx. TM cells thus maintain the resting membrane potential, control Na+ homeostasis, and balance K+ efflux through a novel constitutive monovalent cation leak current with properties not unlike those of TRP channels. Yet to be identified at the molecular level, this novel channel sets the homeostatic steady-state and controls the magnitude of pressure-induced transmembrane signals.

Piezo channels modulate human lung fibroblast function.

Bronchial airways and lung parenchyma undergo both static and dynamic stretch in response to normal breathing as well as in the context of insults such as mechanical ventilation (MV) or in diseases such as asthma and chronic obstructive pulmonary disease (COPD) which lead to airway remodeling involving increased extracellular matrix (ECM) production. Here, the role of fibroblasts is critical, but the relationship between stretch- and fibroblast-induced ECM remodeling under these conditions is not well-explored. Piezo (PZ) channels play a role in mechanotransduction in many cell and organ systems, but their role in mechanical stretch-induced airway remodeling is not known. To explore this, we exposed human lung fibroblasts to 10% static stretch on a background of 5% oscillations for 48 h, with no static stretch considered controls. Collagen I, fibronectin, alpha-smooth muscle actin (α-SMA), and Piezo 1 (PZ1) expression was determined in the presence or absence of Yoda1 (PZ1 agonist) or GsMTx4 (PZ1 inhibitor). Collagen I, fibronectin, and α-SMA expression was increased by stretch and Yoda1, whereas pretreatment with GsMTx4 or knockdown of PZ1 by siRNA blunted this effect. Acute stretch in the presence and absence of Yoda1 demonstrated activation of the ERK pathway but not Smad. Measurement of [Ca2+]i responses to histamine showed significantly greater responses following stretch, effects that were blunted by knockdown of PZ1. Our findings identify an essential role for PZ1 in mechanical stretch-induced production of ECM mediated by ERK phosphorylation and Ca2+ influx in lung fibroblasts. Targeting PZ channels in fibroblasts may constitute a novel approach to ameliorate airway remodeling by decreasing ECM deposition.NEW & NOTEWORTHY The lung is an inherently mechanosensitive organ that can respond to mechanical forces in adaptive or maladaptive ways, including via remodeling resulting in increased fibrosis. We explored the mechanisms that link mechanical forces to remodeling using human lung fibroblasts. We found that mechanosensitive Piezo channels increase with stretch and mediate extracellular matrix formation and the fibroblast-to-myofibroblast transition that occurs with stretch. Our data highlight the importance of Piezo channels in lung mechanotransduction toward remodeling.

Piezo1 expression in neutrophils regulates shear-induced NETosis

Neutrophil infiltration and subsequent extracellular trap formation (NETosis) is a contributing factor in sterile inflammation. Furthermore, neutrophil extracellular traps (NETs) are prothrombotic, as they provide a scaffold for platelets and red blood cells to attach to. In circulation, neutrophils are constantly exposed to hemodynamic forces such as shear stress, which in turn regulates many of their biological functions such as crawling and NETosis. However, the mechanisms that mediate mechanotransduction in neutrophils are not fully understood. In this study, we demonstrate that shear stress induces NETosis, dependent on the shear stress level, and increases the sensitivity of neutrophils to NETosis-inducing agents such as adenosine triphosphate and lipopolysaccharides. Furthermore, shear stress increases intracellular calcium levels in neutrophils and this process is mediated by the mechanosensitive ion channel Piezo1. Activation of Piezo1 in response to shear stress mediates calpain activity and cytoskeleton remodeling, which consequently induces NETosis. Thus, activation of Piezo1 in response to shear stress leads to a stepwise sequence of cellular events that mediates NETosis and thereby places neutrophils at the centre of localized inflammation and prothrombotic effects.

Role of Piezo1 in Terminal Density Reversal of Red Blood Cells.

Density reversal of senescent red blood cells has been known for a long time, yet the identity of the candidate ion transporter(s) causing the senescent cells to swell is still elusive. While performing fractionation of RBCs from healthy individuals in Percoll density gradient and characterization of the separated fractions, we identified a subpopulation of cells in low-density fraction (1.02% ± 0.47) showing signs of senescence such as loss of membrane surface area associated with a reduction in band 3 protein abundance, and Phosphatidylserine (PS) exposure to the outer membrane. In addition, we found that these cells are overloaded with Na+ and Ca2+. Using a combination of blockers and activators of ion pumps and channels, we revealed reduced activity of Plasma membrane Ca2+ ATPase and an increase in Ca2+ and Na+ leaks through ion channels in senescent-like cells. Our data revealed that Ca2+ overload in these cells is a result of reduced PMCA activity and facilitated Ca2+ uptake via a hyperactive Piezo1 channel. However, we could not exclude the contribution of other Ca2+-permeable ion channels in this scenario. In addition, we found, as a universal mechanism, that an increase in intracellular Ca2+ reduced the initially high selectivity of Piezo1 channel for Ca2+ and allowed higher Na+ uptake, Na+ accumulation, and swelling.

Phosphatidic acid is an endogenous negative regulator of PIEZO2 channels and mechanical sensitivity

Mechanosensitive PIEZO2 ion channels play roles in touch, proprioception, and inflammatory pain. Currently, there are no small molecule inhibitors that selectively inhibit PIEZO2 over PIEZO1. The TMEM120A protein was shown to inhibit PIEZO2 while leaving PIEZO1 unaffected. Here we find that TMEM120A expression elevates cellular levels of phosphatidic acid and lysophosphatidic acid (LPA), aligning with its structural resemblance to lipid-modifying enzymes. Intracellular application of phosphatidic acid or LPA inhibits PIEZO2 but not PIEZO1 activity. Extended extracellular exposure to the non-hydrolyzable phosphatidic acid and LPA analog carbocyclic phosphatidic acid (ccPA) also inhibits PIEZO2. Optogenetic activation of phospholipase D (PLD), a signaling enzyme that generates phosphatidic acid, inhibits PIEZO2 but not PIEZO1. Conversely, inhibiting PLD leads to increased PIEZO2 activity and increased mechanical sensitivity in mice in behavioral experiments. These findings unveil lipid regulators that selectively target PIEZO2 over PIEZO1, and identify the PLD pathway as a regulator of PIEZO2 activity.

Ion channels in osteoarthritis: emerging roles and potential targets.

Osteoarthritis (OA) is a highly prevalent joint disease that causes substantial disability, yet effective approaches to disease prevention or to the delay of OA progression are lacking. Emerging evidence has pinpointed ion channels as pivotal mediators in OA pathogenesis and as promising targets for disease-modifying treatments. Preclinical studies have assessed the potential of a variety of ion channel modulators to modify disease pathways involved in cartilage degeneration, synovial inflammation, bone hyperplasia and pain, and to provide symptomatic relief in models of OA. Some of these modulators are currently being evaluated in clinical trials. This review explores the structures and functions of ion channels, including transient receptor potential channels, Piezo channels, voltage-gated sodium channels, voltage-dependent calcium channels, potassium channels, acid-sensing ion channels, chloride channels and the ATP-dependent P2XR channels in the osteoarthritic joint. The discussion spans channel-targeting drug discovery and potential clinical applications, emphasizing opportunities for further research, and underscoring the growing clinical impact of ion channel biology in OA.

Defective CFTR modulates mechanosensitive channels TRPV4 and PIEZO1 and drives endothelial barrier failure

Cystic fibrosis (CF) is a genetic disease caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Despite reports of CFTR expression on endothelial cells, pulmonary vascular perturbations, and perfusion deficits in CF patients, the mechanism of pulmonary vascular disease in CF remains unclear. Here, our pilot study of 40 CF patients reveals a loss of small pulmonary blood vessels in patients with severe lung disease. Using a vessel-on-a-chip model, we establish a shear-stress-dependent mechanism of endothelial barrier failure in CF involving TRPV4, a mechanosensitive channel. Furthermore, we demonstrate that CFTR deficiency downregulates the function of PIEZO1, another mechanosensitive channel involved in angiogenesis and wound repair, and exacerbates loss of small pulmonary blood vessel. We also show that CFTR directly interacts with PIEZO1 and enhances its function. Our study identifies key cellular targets to mitigate loss of small pulmonary blood vessels in CF.

Mechano-adaptation: Exercise-driven Piezo1 & Piezo2 augmentation and chondroprotection in articular cartilage.

Chondrocytes in adult joints are mechanosensitive post-mitotic quiescent cells with robustly expressed both Piezo1 and Piezo2 ion channels. Here, we examined the mechano-adaptation and Piezo modulations in articular chondrocytes using a mouse exercise model. We first found differential expression patterns of PIEZO1 and PIEZO2 in articular chondrocytes of healthy knee joints; chondrocytes in tibial cartilage (T) exhibit significantly higher PIEZO1 and PIEZO2 than femoral chondrocytes (F). Interestingly, a few weeks of exercise caused both PIEZO1 and PIEZO2 augmentation in F and T compared to the sedentary control group. Despite the increased expression levels of these mechanosensors, chondrocytes in exercised cartilage exhibit significantly reduced mechanical susceptibility against 1mJ impact. PIEZO1 modulation was relatively more rapid than PIEZO2 channels post-exercise. We tested the exercise-induced effect using Piezo1-conditional knockout (Pz1-cKO; Agc1 CreERT2 ;Piezo1 fl/fl ). Pz1-cKO mice exhibit diminished exercise-driven chondroprotection against 1mJ impact, suggesting essential roles of Piezo1-mediated mechanotransduction for physiologic-induced cartilage matrix homeostasis. In addition, using a mouse OA model, we further found the modulated PIEZO1 in chondrocytes, consistent with reports in Ren et al., but without PIEZO2 modulations over OA progression. In summary, our data reveal the distinctly tuned Piezo1 and Piezo2 channels in chondrocytes post-exercise and post-injury, in turn modulating the mechanical susceptibility of chondrocytes. We postulate that Piezo1 is a tightly-regulated biphasic biomarker ; Piezo1 antagonism may increase cellular survival post-injury and Piezo1 (with Piezo2) agonism to promote cartilage ECM restoration.

PIEZO1 targeting in macrophages boosts phagocytic activity and foam cell apoptosis in atherosclerosis

The rising incidences of atherosclerosis have necessitated efforts to identify novel targets for therapeutic interventions. In the present study, we observed increased expression of the mechanosensitive calcium channel Piezo1 transcript in mouse and human atherosclerotic plaques, correlating with infiltration of PIEZO1-expressing macrophages. In vitro administration of Yoda1, a specific agonist for PIEZO1, led to increased foam cell apoptosis and enhanced phagocytosis by macrophages. Mechanistically, PIEZO1 activation resulted in intracellular F-actin rearrangement, elevated mitochondrial ROS levels and induction of mitochondrial fragmentation upon PIEZO1 activation, as well as increased expression of anti-inflammatory genes. In vivo, ApoE−/− mice treated with Yoda1 exhibited regression of atherosclerosis, enhanced stability of advanced lesions, reduced plaque size and necrotic core, increased collagen content, and reduced expression levels of inflammatory markers. Our findings propose PIEZO1 as a novel and potential therapeutic target in atherosclerosis.

Piezo ion channels: long-sought-after mechanosensors mediating hypertension and hypertensive nephropathy.

Recent advances in mechanobiology and the discovery of mechanosensitive ion channels have opened a new era of research on hypertension and related diseases. Piezo1 and Piezo2, first reported in 2010, are regarded as bona fide mechanochannels that mediate various biological and pathophysiological phenomena in multiple tissues and organs. For example, Piezo channels have pivotal roles in blood pressure control, triggering shear stress-induced nitric oxide synthesis and vasodilation, regulating baroreflex in the carotid sinus and aorta, and releasing renin from renal juxtaglomerular cells. Herein, we provide an overview of recent literature on the roles of Piezo channels in the pathogenesis of hypertension and related kidney damage, including our experimental data on the involvement of Piezo1 in podocyte injury and that of Piezo2 in renin expression and renal fibrosis in animal models of hypertensive nephropathy. The mechanosensitive ion channels Piezo1 and Piezo2 play various roles in the pathogenesis of systemic hypertension by acting on vascular endothelial cells, baroreceptors in the carotid artery and aorta, and the juxtaglomerular apparatus. Piezo channels also contribute to hypertensive nephropathy by acting on mesangial cells, podocytes, and perivascular mesenchymal cells.