This study, in vivo and in vitro, investigated the role of brain-derived neurotrophic factor (BDNF) in skeletal muscle adaptations to aerobic exercise. BDNF is a contraction-induced protein that may play a role in muscle adaptations to aerobic exercise. BDNF is involved in muscle repair, increased fat oxidation, and mitochondrial biogenesis, all of which are adaptations observed with aerobic training. The purpose of this study was two-pronged and investigated the skeletal muscle BDNF response to (1) acute and (2) chronic exercise in male C57BL/6J mice. It also examined if chronic BDNF treatment resulted in similar adaptations to chronic exercise. In aim 1, mice underwent a 2 hr. treadmill exercise bout. In aim 2, mice were assigned to one of four groups: (1) control (CON); (2) endurance training (ET; treadmill running 1 h/day, 5 days/wk); (3) BDNF (BDNF; 0.5 mg/kg·bw, 5 days/wk); (4) endurance training and BDNF (ET + BDNF) for 8 weeks. Results demonstrated that the soleus (SOL) had higher BDNF content compared with the extensor digitorum longus (EDL) and that SOL BDNF increased with acute exercise. After chronic exercise and BDNF treatment, treadmill testing to exhaustion demonstrated a main effect of BDNF and ET on increasing exercise capacity. In vitro contractile assessment of the EDL revealed BDNF treatment resulted in similar increases in the max rate of relaxation as ET. EDL force-frequency analysis showed ET + BDNF produced higher force than CON and BDNF, indicating an additive effect. BDNF increased EDL mitochondrial proteins, COXIV, and CS. These results demonstrate that BDNF contributes to muscle adaptations observed with ET.

Chemoresistance is an ongoing challenge for colorectal cancer (CRC) that significantly compromises the anti-tumor efficacy of current drugs. Identifying effective targets or drugs for overcoming chemoresistance is urgently needed. Our previous study showed that WFDC3 served as a tumor suppressor that hindered CRC metastasis. However, the function of WFDC3 in chemotherapy remains unknown. Here, we found that high WFDC3 expression in CRC patients treated with oxaliplatin was associated with a better prognosis. Concordantly, overexpression of WFDC3 significantly increased sensitivity to oxaliplatin in CRC cells, whereas knocking down WFDC3 led to oxaliplatin resistance. In addition, WFDC3 promoted oxaliplatin-mediated suppression of tumor growth in vivo. Subsequently, we found that WFDC3 could enhance oxaliplatin-induced DNA damage through inhibiting ATM/ATR signaling. WFDC3 knockdown showed the opposite effects. Moreover, a combination treatment of oxaliplatin and inhibitors for ATM or ATR partially reversed chemoresistance to oxaliplatin in CRC cells with low WFDC3 expression. Our results demonstrate that WFDC3 is possibly a biomarker for increasing oxaliplatin sensitivity in CRC by modulating ATM/ATR kinase signaling. Thus, a combination of oxaliplatin with an ATM or ATR inhibitor is a potential treatment option for improving CRC outcome.

Congenital heart disease (CHD) represents a major birth defect associated with substantial morbidity and mortality. Although environmental factors are acknowledged as potential contributors to CHD, the underlying mechanisms remain poorly understood. Bisphenol A (BPA), a common endocrine disruptor, has attracted significant attention due to its widespread use and associated health risks. This study examined the effects of maternal BPA exposure on fetal heart development in a murine model. The findings indicated that high-dose BPA exposure resulted in fetal growth restriction, myocardial wall thinning, and ventricular septal defects. Transcriptomic analysis revealed downregulation of genes associated with mitochondrial energy synthesis and cardiomyocyte development following high-dose BPA exposure. Functional assays demonstrated that high-dose BPA exposure impaired mitochondrial respiration reduced ATP production, disrupted mitochondrial membrane potential, and increased intracellular reactive oxygen species levels in fetal cardiomyocytes. These results elucidate the detrimental effects of BPA on fetal heart development and mitochondrial function, providing insights into potential mechanisms linking environmental chemical exposure to CHD.

Inflammation is a crucial factor in intracerebral hemorrhage (ICH) pathophysiology, but specific inflammatory biomarkers in ICH patients remain unclear. This study aimed to identify novel circulating inflammatory biomarkers for improved ICH prediction and diagnosis. We profiled expression levels of 92 cardiovascular disease related proteins in plasma from 26 matched ICH patients and controls using Olink technology. Differentially expressed proteins were validated using ELISA and RT-qPCR in a second matched cohort. Receiver operating characteristic (ROC) curves evaluated how well the diagnostic tests performed. The study identified 18 inflammatory-related proteins with significantly different expression levels between ICH patients and controls. These proteins participate in critical biological processes and pathways, such as the regulation of inflammatory mediator secretion, cell death, immune cell proliferation and differentiation, pathogen response, and PI3K-Akt and JAK-STAT pathways. Notably, we discovered for the first time that Kidney Injury Molecule-1 (KIM1) is significantly upregulated in the plasma of ICH patients, suggesting its potential as a predictive and diagnostic biomarker for ICH. Validation results from ELISA and RT-qPCR showed that Interleukin-6 (IL-6), Pentraxin 3 (PTX3), KIM1, and Galectin-9 (Gal-9) concentrations were markedly increased in the blood plasma and white matter of individuals with ICH. ROC analysis showed that the combined marker of IL-6, PTX3, KIM1 and Gal-9 had a high diagnostic efficacy (AUC = 0.941). This study identified a novel biomarker panel (IL-6, PTX3, KIM1, Gal-9) for ICH diagnosis. KIM1 upregulation in ICH patients is a novel finding, further investigation is needed into its expression and function in ICH.

Ghrelin reduced the profibrotic effect of IHC-Exo in liver fibrosis by regulating lncMALAT1/GPX4 pathway mediated HSCs ferroptosis. Triggering HSCs ferroptosis via GHR-IHC-Exo may become a novel strategy to alleviate the progression of liver fibrosis. Liver fibrosis is the end stage of the continuous progression of a variety of chronic liver diseases. With the continuous action of various pathogenic factors, hepatic stellate cells in the liver are activated and produce a large amount of collagen fibers that are deposited in the liver, resulting in obvious damage to liver tissue and leading to cirrhosis and even liver cancer, which seriously affects human health. However, there are still clear and effective drugs approved for the treatment of liver fibrosis, so it is important to explore the possible mechanisms of liver fibrosis treatment. In previous studies, researchers found that exosomes secreted by injured hepatocytes promote the progression of liver fibrosis. In our study, we found that the role of exosomes in promoting liver fibrosis progression was attenuated after pretreatment with Ghrelin. This provides an important theoretical basis for the use of Ghrelin in the treatment of liver fibrosis.

Nuclear factor of activated T-cells 5 (NFAT5) is a transcription factor known for its role in osmotic stress adaptation in the renal inner medulla, due to the osmotic gradient that is generated between the renal cortex and renal inner medulla. However, its broader implications in kidney injury and chronic kidney disease (CKD) are less understood. Here we used two different Cre deleter mice (Ksp1.3-Cre and Aqp2-Cre) to generate tubule segment and even cell type-specific NFAT5-deficient mice and performed extensive gene expression profiling. In both Nfat5 knockout models, we observed massive changes in gene expression pattern, with heightened inflammatory responses and renal injury, culminating in renal fibrosis. Interestingly, inflammatory responses were much more prominent in the Aqp2CreNfat5 mice that lack NFAT5 only in the collecting duct. By analyzing gene expression in the medullary and cortical regions of the kidney separately, we confirmed that the loss of NFAT5 results in kidney injury that extends beyond hypertonic areas. Renal injury correlates with the expression level of genes involved in inflammatory response, injury severity, and cytokine signaling. Thus, NFAT5 is essential not only for adapting to osmotic stress but also for its loss of function, which induces activation of inflammatory response and cytokine signaling that might affect regions with functional NFAT5 expression.

Adipose tissue (AT), is a major endocrine organ that plays a key role in health and disease. However, adipose dysfunctions, especially altered energy metabolism, have been under-investigated as white adipocytes have relatively low mitochondrial density. Nevertheless, recent studies suggest that mitochondria could play a major role in AT disorders and that AT mitochondrial activity could depend on adiposity level and location. This clinical study aimed to evaluate mitochondrial respiration and metabolism in human visceral (vAT) and subcutaneous (scAT) AT and their relationship with body mass index (BMI). This clinical study enrolled 67 patients (30 females/37 males) scheduled for digestive surgery without chemotherapy and parietal infection. BMI ranged from 15.4 to 51.9 kg·m and body composition was estimated by computed tomographic images. Mitochondrial respiration was measured in situ in digitonin-permeabilized AT using high-resolution respirometry and a substrate/inhibitor titration approach. Protein levels of mitochondrial and lipid metabolism key elements were evaluated by Western blot. Maximal mitochondrial respiration correlated negatively with BMI (p < .01) and AT area (p < .001) regardless of the anatomical location. However, oxidative phosphorylation respiration was significantly higher in vAT (2.22 ± 0.15 pmol·sec·mg) than scAT (1.79 ± 0.17 pmol·sec·mg) (p < 0.001). In line with oxygraphy results, there were higher levels of mitochondrial respiratory chain complexes in low-BMI patients and vAT. Mitochondrial respiration decreased with increasing BMI in both scAT and vAT, without sex-associated difference. Mitochondrial respiration appeared to be higher in vAT than scAT. These differences were both qualitative and quantitative. Clinical Trials Registration IDNCT05417581.

Sarcopenia is an age-related muscle atrophy syndrome characterized by the loss of muscle strength and mass. Although many agents have been used to treat sarcopenia, there are no successful treatments to date. In this study, we identified Danshensu sodium salt (DSS) as a substantial suppressive agent of muscle atrophy. We used a D-galactose (DG)-induced aging-acceleration model, both in vivo and in vitro, to confirm the effect of DSS on sarcopenia. DSS inhibits the expression of muscle atrophy-related factors (MuRF1, MAFbx, myostatin, and FoxO3a) in DG-induced mouse C2C12 and human skeletal muscle cells. Additionally, DSS restored the diameter of reduced C2C12 myotubes. Next, we demonstrated that DSS stimulates AMPK and PGC1α through CaMKII. DSS inhibits the translocation of FoxO3a into the nucleus, thus inhibiting muscle atrophy in a calcium-dependent manner. DSS initiated the protein-protein interaction between FoxO3a and PGC1α. The reduction of the PGC1α-FoxO3a interaction by DG was restored by DSS. Also, DSS suppressed increased intracellular reactive oxygen species (ROS) by DG. In animal models, DSS administration improved mouse muscle mass and physical performance (grip strength and hanging test) under DG-induced accelerated aging conditions. These findings demonstrated that DSS attenuates muscle atrophy by inhibiting the expression of muscle atrophy-related factors. Therefore, DSS may be a potential therapeutic agent for the treatment of sarcopenia.

With the emergence of high-quality sequencing technologies, further research on transcriptomes has become possible. Circular RNA (circRNA), a novel type of endogenous RNA molecule with a covalently closed circular structure through "back-splicing," is reported to be widely present in eukaryotic cells and participates mainly in regulating gene and protein expression in various ways. It is becoming a research hotspot in the non-coding RNA field. CircRNA shows close relation to several varieties of autoimmune diseases (AIDs) in both the physiological and pathological level and could potentially be used clinically in terms of diagnosis and treatment. Here, we focus on reviewing the importance of circRNA in various AIDs, with the aim of establishing new biomarkers and providing novel insights into understanding the role and functions of circRNA in AIDs. Specific signaling pathways of how circular RNAs are regulated in AIDs will also be illustrated in this review.

Among the known nuclear exportins, CRM1 is the most studied prototype. Dysregulation of CRM1 occurs in many cancers, hence, understanding the role of CRM1 in cancer can help in developing synergistic therapeutics. The study investigates how CRM1 affects prostate cancer growth and survival. It examines the role of CRM1 in regulating androgen receptor (AR) and DNA repair in prostate cancer. Our findings reveal that CRM1 influences AR mRNA and protein stability, leading to a loss of AR protein upon CRM1 inhibition. Furthermore, it highlights the involvement of HSP90 alpha, a known AR chaperone, in the CRM1-dependent regulation of AR protein stability. The combination of CRM1 inhibition with an HSP90 inhibitor demonstrates potent effects on decreasing prostate cancer cell growth and survival. The study further explores the influence of CRM1 on DNA repair proteins and proposes a strategy of combining CRM1 inhibitors with DNA repair pathway inhibitors to decrease prostate cancer growth. Overall, the findings suggest that CRM1 plays a crucial role in prostate cancer growth, and a combination of inhibitors targeting CRM1 and DNA repair pathways could be a promising therapeutic strategy.

Triglyceride (TG) metabolism is a complex and highly coordinated biological process regulated by a series of genes, and its dysregulation can lead to the occurrence of disorders in lipid metabolism. However, the transcriptional regulatory mechanisms of crucial genes in TG metabolism mediated by enhancer-promoter interactions remain elusive. Here, we identified candidate enhancers regulating the Agpat2, Dgat1, Dgat2, Pnpla2, and Lipe genes in 3T3-L1 adipocytes by integrating epigenomic data (H3K27ac, H3K4me1, and DHS-seq) with chromatin three-dimensional interaction data. Luciferase reporter assays revealed that 11 enhancers exhibited fluorescence activity. The repression of enhancers using the dCas9-KRAB system revealed the functional roles of enhancers of Dgat2 and Pnpla2 in regulating their expression and TG metabolism. Furthermore, transcriptome analyses revealed that inhibition of Dgat2-En4 downregulated pathways associated with lipid metabolism, lipid biosynthesis, and adipocyte differentiation. Additionally, overexpression and motif mutation experiments of transcription factor found that two TFs, PPARG and RXRA, regulate the activity of Agpat2-En1, Dgat2-En4, and Pnpla2-En5. Our study identified functional enhancers regulating TG metabolism and elucidated potential regulatory mechanisms of TG deposition from enhancer-promoter interactions, providing insights into understanding lipid deposition.

Pulmonary fibrosis (PF) is a chronic and progressive interstitial lung disease characterized by abnormal activation of myofibroblasts and pathological remodeling of the extracellular matrix, with a poor prognosis and limited treatment options. Lung transplantation is currently the only approach that can extend the life expectancy of patients; however, its applicability is severely restricted due to donor shortages and patient-specific limitations. Therefore, the search for novel therapeutic strategies is imperative. In recent years, stem cells have shown great promise in the field of regenerative medicine due to their self-renewal capacity and multidirectional differentiation potential, and a growing body of literature supports the efficacy of stem cell therapy in PF treatment. This paper systematically summarizes the research progress of various stem cell types in the treatment of PF. Furthermore, it discusses the primary methods and clinical outcomes of stem cell therapy in PF, based on both preclinical and clinical data. Finally, the current challenges and key factors to consider in stem cell therapy for PF are objectively analyzed, and future directions for improving this therapy are proposed, providing new insights and references for the clinical treatment of PF patients.

This study aimed to investigate the effects of electroacupuncture (EA) at specific acupoints (DU20 and ST36) and different frequencies (2 and 100 Hz) on brain regions associated with trigeminal neuralgia, anxiety, and depression. Chronic trigeminal neuralgia was induced by the chronic constriction of the infraorbital nerve (CION). Anxiety and depression were assessed through behavioral tests. The effects of high-frequency (100 Hz) and low-frequency (2 Hz) EA at DU20 and ST36 were compared using immunofluorescence staining to evaluate their impact on pain, anxiety, depression, and brain activity. CION induced prominent trigeminal neuralgia in mice, accompanied by anxiety- and depression-like behaviors. Two weeks post-CION surgery increased neural activity was observed in the Prl, Cg1, CeA, BLA, TRN, CA3, CA1, vlPAG, PC5, and LPB brain regions, while reduced activity was noted in the PVN, VTA, and LDTgv regions. EA at 100 Hz applied to DU20 and ST36 rapidly alleviated pain and specifically reduced despair behavior, a depressive-like phenotype. In contrast, 2 Hz EA at the same acupoints addressed both anxiety- and depression-like behaviors, modulating a broader range of brain regions, including the PrL, BLA, PVN, VTA, vlPAG, and LDTgv, compared to 100 Hz EA. Repeated 2 Hz EA exclusively at DU20 was sufficient for analgesia and improvement of anxiety and depression, demonstrating a more extensive modulation of brain activity, particularly in the VTA and LDTgv, than EA at ST36. The study reveals that CION induces significant trigeminal neuralgia, accompanied by anxiety and depression, characterized by distinct neural activity patterns. EA at 2 Hz exhibits greater effectiveness in alleviating anxiety and depression, exerting broad modulation across various brain regions. Notably, EA at DU20 demonstrates superior modulation of brain activity and enhanced antidepressant and analgesic effects compared to ST36. These findings provide valuable insights into the nuanced therapeutic effects of EA on the interplay between chronic pain and affective disorders, suggesting potential clinical strategies for intervention.

Gestational Diabetes Mellitus (GDM) is the most frequent complication during pregnancy. Pharmacological interventions, such as peptide drugs that focused on improving the insulin sensitivity might be promising in the prevention and treatment of GDM. In this study, we aimed to investigate the role and mechanism of a novel peptide, named AGDMP1 (Anti-GDM peptide 1), which we previously identified lower in the serum of GDM patients using mass spectrometry, on the adipose insulin resistance in GDM. We found that AGDMP1 had a high affinity for adipose tissues in vivo. AGDMP1 markedly improved glucose homeostasis and insulin resistance in GDM mice. This was associated with reduced inflammation and upregulated AKT/GLUT4 signaling pathway in white adipose tissue. In vitro, AGDMP1 could increase glucose uptake and insulin sensitivity of adipocytes by activating the IRS-1/AKT/GLUT4 signaling pathway under basal, insulin-stimulated, and insulin-resistant conditions, respectively. Mechanistically, we found that AGDMP1 could bind to HSP60 to dampen its effects on AKT signaling and pro-inflammatory response, which was reversed in the present of recombinant HSP60 protein. AGDMP1 ameliorated adipose insulin resistance and inflammation by targeting HSP60 and activating the IRS-1/AKT/GLUT4 signaling pathway. These data supported AGDMP1 with therapeutic potential in GDM and associated pathologies.

The smooth muscle cells (SMCs) located in the vascular media layer are continuously subjected to cyclic stretching perpendicular to the vessel wall and play a crucial role in vascular wall remodeling and blood pressure regulation. Mesenchymal stem cells (MSCs) are promising tools to differentiate into SMCs. Mechanical stretch loading offers an opportunity to guide the MSC-SMC differentiation and mechanical adaption for function regeneration of blood vessels. This study shows that cyclic stretch induces the expression of SMC markers α-SMA and SM22 in MSCs. These cells exhibit contractile ability in vitro and facilitate angiogenesis in the Matrigel plug assay in vivo. The contraction of SMCs requires remodeling of their energy metabolism. However, the underlying mechanism in the differentiation of MSCs into SMCs remains to be revealed. Cyclic stretch training promotes glycolysis, oxidative phosphorylation, and mitochondrial fusion and modulates mitochondrial dynamics-related proteins (MFN1, MFN2, DRP1) expression, thereby contributing to MSCs differentiation. Yes-associated protein (YAP) affects mitochondrial dynamics, oxidative phosphorylation, and glycolysis to regulate stretch-mediated differentiation into SMCs. Additionally, Piezo-type mechanosensitive ion channel component 1 (Piezo1) impacts energy metabolism and MSCs differentiation by regulating intracellular Ca levels and YAP nuclear localization. It indicates that YAP can integrate stretch force and energy metabolism signals to regulate the differentiation of MSCs into SMCs.

Liver ischemia-reperfusion (IR) injury is a common complication following liver surgery, significantly impacting the prognosis of liver transplantation and other liver surgeries. Betaine-homocysteine methyltransferase (BHMT), a crucial enzyme in the methionine cycle, has been previously confirmed the pivotal role in hepatocellular carcinoma, and it has also been demonstrated that BHMT inhibits inflammation, apoptosis, but its role in liver IR injury remains unknow. Following I/R injury, we found that BHMT expression was significantly upregulated in human liver transplant specimens, mice and hepatocytes. Utilizing BHMT knockout mice, we established an in vivo model of liver IR injury, and with BHMT knockout and overexpression AML12 cell lines, we created an in vitro hypoxia-reoxygenation model. Our findings reveal that BHMT deficiency exacerbates liver IR injury, leading to increased reactive oxygen species, apoptosis and inflammation, whereas BHMT overexpression mitigates these effects. We observed that BHMT inhibits the c-Jun N-terminal kinase (JNK)/p38 signaling pathway in liver IR injury by interacting with TAK1 and inhibiting its activity. The application of 5z-7-ox, a TAK1 inhibitor, reversed the worsening of liver IR injury and the activation of the JNK/p38 pathway associated with BHMT deficiency. These results demonstrate that BHMT protects against liver IR injury by targeting TAK1 and inhibiting the JNK/p38 signaling pathway. Our findings suggest that BHMT may be a promising therapeutic target for preventing liver IR injury.

Milk is a multifaceted biofluid that is essential for infant nutrition and development, yet its cellular and bioactive components, particularly maternal milk cells, remain understudied. Early research on milk cells indicated that they cross the infant's intestinal barrier and accumulate within systemic organs. However, due to the absence of modern analytical techniques, these studies were limited in scope and mechanistic analysis. To overcome this knowledge gap, we have investigated the transintestinal transport of milk cells and components in pups over a 21-day period. Studies employed a mT/mG foster nursing model in which milk cells express a membrane-bound fluorophore, tdTomato. Using flow cytometry, we tracked the transport of milk cell-derived components across local and systemic tissues, including the intestines, blood, thymus, mesenteric lymph nodes, and liver. These experiments identified milk-derived fluorescent signals in intestinal epithelial and immune cells as well as liver macrophages in 7-day-old pups. However, the minute numbers of macrophages in mouse milk suggest that maternal cells are not systemically accumulating in the infant; instead, pup macrophages are consuming milk cell membrane components, such as apoptotic bodies or extracellular vesicles (EVs). Ex vivo experiments using primary macrophages support this hypothesis, showing that immune cells preferentially consumed EVs over milk cells. Together, these data suggest a more complex interplay between milk cells and the infant's immune and digestive systems than previously recognized and highlight the need for future research on the role of milk cells in infant health.

Circulating monocytes contribute to the defense against pathogens and play a crucial role in maintaining immune homeostasis. While there is substantial evidence regarding the triggers of monocyte activation, our understanding of how monocyte function is restored toward homeostasis after activation remains limited. Here, we assessed the changes in monocyte anisocytosis upon activation in blood, measured by monocyte distribution width (MDW), a biomarker for sepsis. We determined that the increase in MDW post-lipopolysaccharide (LPS) stimulation in the blood can be reversed promptly by adding resolvin D2 (RvD2), and we measured a decrease in interleukin-1 beta (IL-1β) in blood, and a decrease in the size of the population of intermediate monocyte subsets. Moreover, the ex vivo addition of RvD2 to blood samples from burn patients with high MDW restored normal MDW values. Further studies are needed to probe the potential therapeutic role of RvD2 in the context of burn injuries.

The kinases AMPK, and mTOR as part of either mTORC1 or mTORC2, are major orchestrators of cellular growth and metabolism. Phosphorylation of mTOR Ser1261 is reportedly stimulated by both insulin and AMPK activation and a regulator of both mTORC1 and mTORC2 activity. Intrigued by the possibilities that Ser1261 might be a convergence point between insulin and AMPK signaling in skeletal muscle, we investigated the regulation and function of this site using a combination of human exercise, transgenic mouse, and cell culture models. Ser1261 phosphorylation on mTOR did not respond to insulin in any of our tested models, but instead responded acutely to contractile activity in human and mouse muscle in an AMPK activity-dependent manner. Contraction-stimulated mTOR Ser1261 phosphorylation in mice was decreased by Raptor muscle knockout (mKO) and increased by Raptor muscle overexpression, yet was not affected by Rictor mKO, suggesting most of Ser1261 phosphorylation occurs within mTORC1 in skeletal muscle. In accordance, HEK293 cells mTOR Ser1261Ala mutation strongly impaired phosphorylation of mTORC1 substrates but not mTORC2 substrates. However, neither mTORC1 nor mTORC2-dependent phosphorylations were affected in muscle-specific kinase-dead AMPK mice with no detectable mTOR Ser1261 phosphorylation in skeletal muscle. Thus, mTOR Ser1261 is an exercise but not insulin-responsive AMPK-dependent phosphosite in human and murine skeletal muscle, playing an unclear role in mTORC1 regulation but clearly not required for mTORC2 activity.

Spaceflight-induced multi-organ dysfunction affects the health of astronauts and the safety of in-orbit flight. However, the effect of microgravity on the kidney and the underlying mechanisms are unknown. In the current study, we used a hindlimb unweighting (HU) animal model to simulate microgravity and employed histological analysis, ischemia-reperfusion experiments, renal ultrasonography, bioinformatics analysis, isometric force measurement, and other molecular experimental settings to evaluate the effects of microgravity on the kidneys and the underlying mechanisms involved in this transition. Relative to controls, 31-day hindlimb unweighting had no obvious effect on serum creatinine and urea nitrogen levels as well as on renal injury scores; however, animals in the HU group showed an impaired renal recovery to ischemia-reperfusion injury. Ultrasonography showed that renal resistive index was increased, which indicated an altered renal hemodynamics induced by simulated microgravity. The enhanced vasoconstriction mediated by the Rho-kinase pathway and impaired vasodilation mediated by NO-eNOS of the intrarenal artery contributed to the altered renal hemodynamics. Simulated microgravity predisposes the kidney to ischemia-reperfusion injury. The altered renal hemodynamics induced by renal arterial remodeling may account for the increased renal injury susceptibility, providing a target for early intervention in kidney dysfunction under microgravity.