Background and Hypothesis: Resuscitation strategies incorporating fresh frozen plasma have become the standard of care in the management of traumatic hemorrhagic shock. While plasma resuscitation has been shown to augment the circulation and reduce inflammation within the splanchnic and pulmonary circulation, its global effect on the kidney remains unknown. We hypothesized that plasma would improve intrarenal blood flow and reduce parenchymal inflammation when compared to resuscitation with lactated ringer's. Methods: Animals were randomized into four groups (n = 8): a) baseline, b) hemorrhagic shock alone, c) lactated ringer's resuscitation, and d) fresh frozen plasma resuscitation. Multiplex immunoassays were used to evaluate cytokine and chemokine signaling within the renal cortex and immunohistochemistry was used to identify leukocyte infiltration. Doppler ultrasonography was used to evaluate changes in blood flow and maximum kidney diameter during hemorrhagic shock and resuscitation. Results: While no difference in resistive index (surrogate for blood flow) within the renal artery or parenchymal vessels was observed between resuscitation strategies, plasma resulted in increased transverse kidney diameter. Plasma administration promoted cytokine/chemokine signaling, resulting in increased infiltration of leukocytes within the renal cortex when compared to lactated ringer's. Conclusion: Although the clinical benefits of plasma resuscitation mandate its utilization, our current findings highlight the complexities of plasma resuscitation. While the increase in renal diameter may be related to augmentation of the microcirculation, plasma resuscitation did not enhance macro-circulatory blood flow. Furthermore, plasma resuscitation appears to exacerbate inflammation within the renal cortex after hemorrhage. The downstream physiologic implications of plasma-induced inflammation warrant further exploration.

We established a swine model of traumatic hemorrhagic shock to assess secondary renal injury under dry-heat conditions to clarify the roles of cell pyroptosis and inflammatory response in traumatic hemorrhagic shock development. Sixty-eight domestic Landrace piglets were divided into normothermic environment, dry-heat sham surgery, and dry-heat environment traumatic hemorrhagic shock groups (four subgroups: 3 h of environmental exposure and 60, 120, and 180 min after inducing traumatic hemorrhagic shock). The kidneys and blood were sampled at various time points. Univariate analysis of variance or non-parametric test was used for intergroup and intragroup comparisons, and the least significant difference test was used for multiple comparisons. The serum lipopolysaccharide, neutrophil gelatinase-associated lipocalin, kidney injury molecule 1, blood urea nitrogen, and creatinine levels, as well as various inflammatory factors, oxidative stress indicators, and Paller score, were significantly higher under dry-heat environment traumatic hemorrhagic shock than under normothermic environment and dry-heat sham surgery at 180 min. The histopathological damage in the dry-heat environment traumatic hemorrhagic shock group increased significantly at 180 min. Immunohistochemistry, western blotting, and terminal deoxynucleotidyl transferase dUTP nick end labeling assays showed that protein expression and apoptosis index values in the renal tissues of all three groups increased but were significantly higher under dry-heat environment traumatic hemorrhagic shock than under normothermic environment and dry-heat sham surgery at 180 min. The combination of dry-heat environment and traumatic hemorrhagic shock induces an aggravation of secondary renal injury, which may be related to cell pyroptosis, inflammatory response, apoptosis, and oxidative stress. Our findings may assist in the development of treatments for acute kidney injury.

Acute kidney injury (AKI) is a clinical syndrome that is defined as a sudden decline in renal function and characterized by inflammation and tubular injury. Alginate oligosaccharide (AOSC), a natural product obtained from alginate by acidolysis and hydrolysis, shows activities of antioxidant, immunomodulation, and anti-inflammation. In this study, we investigated the potential of AOSC in the treatment of AKI. Renal ischemia-reperfusion (I/R) was induced in male rats by clipping both the renal artery and vein for 45 min followed by reperfusion for 24 h. The rats were treated with AOSC (100 mg/kg, i.g.) before surgery. At the end of the experiments, both kidneys were collected for protein, mRNA measurement, or histological analysis. We showed that AOSC pretreatment significantly improved glomerular and tubular function in the kidney of I/R rats. AOSC markedly inhibited I/R-induced activation of TLR4/MyD88/NF-κB/IL-1β inflammatory signaling and prevented apoptosis in the kidney. In HK2 cells subjected to hypoxia/reoxygenation (H/R) stimulation, AOSC (250-1000 μg/ml) dose-dependently prevented pro-inflammatory responses and cell apoptosis. Transcriptomic analysis revealed that I/R increased the expression levels of mannose receptor type C1 (MRC1) in the kidney, which was markedly inhibited by AOSC. Molecular docking showed that AOSC interacted with E725, N727, E733, T743, S745, and N747 of MRC1 through hydrogen bonds. MRC1 gene knockout significantly improved renal function and attenuated I/R-induced kidney inflammation and apoptosis in mice. In line with this, AOSC failed to prevent I/R-induced kidney injury in MRC1 gene knockout mice. UPLC analysis showed that the protection of AOSC in HK2 cells subjected to H/R was likely attributed to MRC1-mediated intracellular endocytosis. In conclusion, AOSC prevents I/R-induced AKI, which is at least partially mediated by MRC1.

Renal inflammatory diseases are a group of severe conditions marked by significant morbidity and mortality. Extracellular vesicles (EVs), as facilitators of intercellular communication, have been recognized as pivotal regulators of renal inflammatory diseases, significantly contributing to these conditions by modulating immune responses among other mechanisms. This review highlights the intricate mechanisms through which EVs modulate macrophage-kidney cell interactions by regulating macrophages, the principal immune cells within the renal milieu. This regulation subsequently influences the pathophysiology of renal inflammatory diseases such as acute kidney injury and chronic kidney disease. Furthermore, understanding these mechanisms offers novel opportunities to alleviate the severe consequences associated with renal inflammatory diseases. In addition, we summarize the therapeutic landscape based on EV-mediated macrophage regulatory mechanisms, highlighting the potential of EVs as biomarkers and therapeutic targets as well as the challenges and limitations of translating therapies into clinical practice.

Acute kidney injury (AKI) resulting from ischemia-reperfusion injury (IRI) is a common challenge in various clinical practices, yet effective therapies remain elusive. Endothelial injury plays a crucial role in the pathogenesis of renal IRI. Endothelial progenitor cells (EPCs) derived extracellular vesicles (EVs) hold promise as cell-free therapies for treating renal IRI; however, their efficacy is limited by low delivery efficiency. In this study, we developed neutrophils (NEs) membrane-modified EVs (N-EVs) by exploiting the natural properties of NEs to target damaged endothelium. N-EVs inherited the characteristic membrane proteins of NEs along with the biological functions of EPCs-EVs. Results from in vitro and in vivo experiments demonstrated that N-EVs significantly enhanced the targeting efficiency of EVs towards IRI kidneys via P-selectin glycoprotein ligand-1 (PSGL-1). Moreover, N-EVs effectively promoted the proliferation, migration, and tube-formation abilities of injured endothelial cells (ECs) and contributed to overall renal function improvement in IRI kidneys through targeted delivery of miR-21-5p. Additionally, N-EVs could restore damaged endothelial integrity, reduce cytokine release, and inhibit leukocyte infiltration, hence alleviating renal inflammation. In conclusion, our accessible engineering approach represents a promising strategy for treating renal IRI. Furthermore, this membrane hybrid modification can be tailored and optimized for broader applications in treating other diseases.

Objective: To assess the link between systemic immune-inflammation index (SII) and risk of major adverse cardiovascular events (MACE), contrast-induced nephropathy (CIN), and overall mortality in patients with acute myocardial infarction (AMI). Patients and Methods: Electronic search of PubMed, EMBASE, Web of Science, and Scopus databases was done for observational studies with the data on the association of SII and outcomes, such as MACE, and CIN in adult (≥18 y) patients with AMI. A random-effects model was used, and the pooled effect sizes were expressed as relative risk (RR) with corresponding 95% confidence intervals (CI). Subgroup analysis was conducted on the basis of the type of AMI (ST elevation myocardial infarction and non-ST elevation myocardial infarction), sample size (≥500 and <500), and study design. GRADE assessment was used to evaluate the certainty of the evidence. Results: The analysis included 23 studies. Most studies were conducted in China (n = 13), followed by Turkey (n = 10). Majority of the studies (n = 20) had a retrospective cohort design. Patients with high SII had increased risk of MACE (RR 2.95, 95% CI: 1.25, 6.99; n = 5, I2 = 97.5%), overall mortality (RR 2.59, 95% CI: 1.64, 4.07; n = 6, I2 = 58.0%), and CIN (RR 4.58, 95% CI: 3.44, 6.10; n = 4, I2 = 0.0%), compared with patients with lower SII. Egger's test detected publication bias for MACE (p = 0.047) and overall mortality (p = 0.012) but not for CIN. These associations remained valid in subgroup analysis. Conclusion: Findings suggest that higher SII in patients with AMI is associated with increased risks of MACE, CIN, and overall mortality. This underscores SII's potential as a prognostic marker in AMI.

Acute kidney injury (AKI) is a common and severe clinical condition. However, the underlying mechanisms of AKI have not been fully elucidated, and effective treatment options remain limited. Studies have shown that immune cells play a critical role in AKI, with regulatory T cells (Tregs) being one of the most important immunosuppressive lymphocytes. Tregs proliferation can attenuate AKI, whereas depletion exacerbates kidney injury. Given that endothelial cells (ECs) are the initial cells that interact with immune cells when they invade the tissue parenchyma, ECs are closely associated with immune reactions.

In this study, P-selectin binding peptide-extracellular vesicles (PBP-EVs) that target and repair ECs are engineered. Transcriptome sequencing reveals that PBP-EVs reduce the expression of inflammatory genes in AKI mice. Using high-resolution intravital two-photon microscopy (TPM), an increased recruitment of Tregs in the kidneys of AKI Foxp3-EGFP transgenic mice following PBP-EVs treatment is observed, as well as significant Lgr5+ renal stem cell proliferation in AKI Lgr5-CreERT2; R26mTmG mice. Additionally, PBP-EVs treatment result in reduced infiltration of inflammatory cells, pathological damage and fibrosis of AKI mice. Upon depletion of Tregs in Foxp3-DTR transgenic mice, we observe diminished therapeutic effect of PBP-EVs on AKI.

The experimental results indicate that PBP-EVs can promote the repair and regeneration of AKI by mitigating endothelial cell damage and subsequently modulating Tregs and the immune microenvironment. These findings provide novel insights and strategies for the treatment of AKI.

The prevalence of drug-induced liver injury (DILI) and viral liver infections presents significant challenges in modern healthcare and contributes to considerable morbidity and mortality worldwide. Concurrently, metabolic dysfunctionassociated steatotic liver disease (MASLD) has emerged as a major public health concern, reflecting the increasing rates of obesity and leading to more severe complications such as fibrosis and hepatocellular carcinoma. X-box binding protein 1 (XBP1) is a distinct transcription factor with a basic-region leucine zipper structure, whose activity is regulated by alternative splicing in response to disruptions in endoplasmic reticulum (ER) homeostasis and the unfolded protein response (UPR) activation. XBP1 interacts with a key signaling component of the highly conserved UPR and is critical in determining cell fate when responding to ER stress in liver diseases. This review aims to elucidate the emerging roles and molecular mechanisms of XBP1 in liver pathogenesis, focusing on its involvement in DILI, viral liver infections, MASLD, fibrosis/cirrhosis, and liver cancer. Understanding the multifaceted functions of XBP1 in these liver diseases offers insights into potential therapeutic strategies to restore ER homeostasis and mitigate liver damage.

MicroRNA-21 (miR-21) is one of the most frequently upregulated miRNAs in response to kidney ischemia-reperfusion (IR) injury, exhibiting both protective and pathogenic effects depending on the cell type, disease state, and target signaling. In this study, we analyzed the function of miR-21 in various cell types to elucidate its role in ischemia-induced inflammation and acute kidney injury (AKI). Utilizing a mouse model of IR injury, we observed significant upregulation of miR-21 in renal tubular epithelial cells and macrophages following IR. Deletion of miR-21 in macrophages mitigated IR-induced pro-inflammatory cytokine production and AKI. However, conditional deletion of miR-21 in proximal tubules or nonproximal tubules did not protect the kidneys against these effects. Mechanistically, miR-21 inhibition promoted M2-like polarization in macrophages and suppressed M1-like polarization and proinflammatory cytokine production in kidneys. In vitro, miR-21 knockdown in the mouse macrophage cell line Raw246.7 or genetic deletion of miR-21 in bone marrow-derived macrophages (BMDMs) increased the percentage of CD206+ cells (M2 phenotype) while decreasing the percentage of CD86+ cells (M1 phenotype) and the expressions of proinflammatory cytokines. Overexpression of miR-21 in Raw264.7 cells reduced the percentage of CD206+ cells. Furthermore, we demonstrated that signal transducer and activator of transcription 3 (STAT3) was a target gene of miR-21 in macrophages, and miR-21 deletion promoted M2 macrophage polarization via STAT3 activation. In conclusion, miR-21 plays a role in regulating macrophage polarization, and the blockade of miR-21/STAT3 signaling may represent a novel therapeutic strategy for the prevention or treatment of AKI.

Diabetes mellitus (DM) is acknowledged as an independent risk factor for acute kidney injury. Ras guanine nucleotide-releasing protein-4 (RasGRP4) exerts a notable role in modulating immune-inflammatory responses and kidney disease progression in diabetes. Herein, we delved into the specific role and mechanism of RasGRP4 in diabetic renal ischemia-reperfusion injury. Diabetes was induced by a high-fat diet and streptozocin (STZ) injections, followed by creating an ischemia-reperfusion kidney injury via renal pedicle clamping and reperfusion. In vitro, a high glucose and hypoxia-reoxygenation modeled cellular inflammatory injury. We found RasGRP4-KO mice, compared with C57BL/6J (WT) mice, showed markedly less renal dysfunction and fibrosis in diabetic ischemia-reperfusion injury. There was a significant decrease in the renal infiltration of M1 macrophages and Th17 cells, along with downregulated IL-17 pathway proteins and effectors. In vitro, RasGRP4 deletion restrained M1 macrophage polarization and Th17 cell differentiation, inhibiting the IL-17 signaling pathway in HK-2 cells. Hyperglycemia intensified renal inflammation state. Together, RasGRP4, through the regulation of interactions among M1 macrophages, CD4+ T cells, and HK-2 cells, formed a cascade that intensified the inflammatory storm activity, ultimately exacerbating the inflammatory injury of diabetic ischemia-reperfusion kidneys. DM intensified this inflammatory injury mechanism, worsening the injury from renal ischemia-reperfusion.

Severe acute kidney injury (AKI) requiring postoperative renal replacement therapy (RRT) is associated with increased morbidity and mortality rates following cardiac surgery. Our study aimed to analyze patients requiring postoperative RRT in a population undergoing isolated coronary artery surgery.

Following exclusions, we analyzed 124 944 consecutive patients in the Polish National Registry of Cardiac Surgical Procedures (KROK Registry), scheduled for isolated coronary artery surgery between January 2010 and December 2019. Patients who underwent preoperative chronic dialysis were excluded from the study. Data of patients requiring postoperative RRT and patients without postoperative RRT were compared.

In the analyzed population, 1668 patients (1.3%) developed AKI requiring RRT. In-hospital mortality among patients with and without postoperative RRT was 40.1 and 1.6%, respectively ( P <0.001). Patients requiring postoperative RRT had significantly more preoperative co-morbidities and more frequent postoperative complications. Preoperative chronic renal failure and cardiogenic shock were the two most prominent independent risk factors for postoperative RRT in these patients (OR: 5.0, 95% CI: 3.9-6.4, P <0.001 and OR: 3.9, 95% CI: 2.8-5.6, P <0.001, respectively).

Severe AKI requiring postoperative RRT dramatically increases in-hospital mortality and is associated with the development of serious postoperative complications. The need for postoperative RRT is clearly associated with the presence of preoperative co-morbidities. Preoperative chronic renal failure and cardiogenic shock were particularly related to the development of this complication.

Renal ischemia-reperfusion injury (RIRI) is a critical phenomenon that compromises renal function and is the most serious health concern related to acute kidney injury (AKI). Pioglitazone (Pio) is a known agonist of peroxisome proliferator-activated receptor-gamma (PPAR-γ). PPAR-γ is a nuclear receptor that regulates genes involved in inflammation, metabolism, and cellular differentiation. Activation of PPAR-γ is associated with antiinflammatory and antioxidant effects, which are relevant to the pathophysiology of RIRI. This study aimed to investigate the protective effects of Pio in RIRI, focusing on oxidative stress and inflammation.

We conducted a comprehensive literature search using electronic databases, including PubMed, ScienceDirect, Web of Science, Scopus, and Google Scholar.

The results of this study demonstrated that Pio has antioxidant, anti-inflammatory, and anti-apoptotic activities that counteract the consequences of RIRI. The study also discussed the underlying mechanisms, including the modulation of various pathways such as TNF-α, NF-κB signaling systems, STAT3 pathway, KIM-1 and NGAL pathways, AMPK phosphorylation, and autophagy flux. Additionally, the study presented a summary of various animal studies that support the potential protective effects of Pio in RIRI.

Our findings suggest that Pio could protect the kidneys from RIRI by improving antioxidant capacity and decreasing inflammation. Therefore, these findings support the potential of Pio as a therapeutic strategy for preventing RIRI in different clinical conditions.

Acute kidney injury (AKI) is a major worldwide health concern that currently lacks effective medical treatments. PSMP is a damage-induced chemotactic cytokine that acts as a ligand of CCR2 and has an unknown role in AKI. We have observed a significant increase in PSMP levels in the renal tissue, urine, and plasma of patients with AKI. PSMP deficiency improved kidney function and decreased tubular damage and inflammation in AKI mouse models induced by kidney ischemia-reperfusion injury, glycerol, and cisplatin. Single-cell RNA sequencing analysis revealed that Ly6Chi or F4/80lo infiltrated macrophages (IMs) were a major group of proinflammatory macrophages with strong CCR2 expression in AKI. We observed that PSMP deficiency decreased CCR2+Ly6Chi or F4/80lo IMs and inhibited M1 polarization in the AKI mouse model. Moreover, overexpressed human PSMP in the mouse kidney could reverse the attenuation of kidney injury in a CCR2-dependent manner, and this effect could be achieved without CCL2 involvement. Extracellular PSMP played a crucial role, and treatment with a PSMP-neutralizing antibody significantly reduced kidney injury in vivo. Therefore, PSMP might be a therapeutic target for AKI, and its antibody is a promising therapeutic drug for the treatment of AKI.

Elevated interferon (IFN) signaling is associated with kidney diseases including COVID-19, HIV, and apolipoprotein-L1 (APOL1) nephropathy, but whether IFNs directly contribute to nephrotoxicity remains unclear. Using human kidney organoids, primary endothelial cells, and patient samples, we demonstrate that IFN-γ induces pyroptotic angiopathy in combination with APOL1 expression. Single-cell RNA sequencing, immunoblotting, and quantitative fluorescence-based assays reveal that IFN-γ-mediated expression of APOL1 is accompanied by pyroptotic endothelial network degradation in organoids. Pharmacological blockade of IFN-γ signaling inhibits APOL1 expression, prevents upregulation of pyroptosis-associated genes, and rescues vascular networks. Multiomic analyses in patients with COVID-19, proteinuric kidney disease, and collapsing glomerulopathy similarly demonstrate increased IFN signaling and pyroptosis-associated gene expression correlating with accelerated renal disease progression. Our results reveal that IFN-γ signaling simultaneously induces endothelial injury and primes renal cells for pyroptosis, suggesting a combinatorial mechanism for APOL1-mediated collapsing glomerulopathy, which can be targeted therapeutically.

Delayed graft function (DGF) is a form of acute kidney injury (AKI) and a common complication following kidney transplantation. It adversely influences patient outcomes increases the financial burden of transplantation, and currently, no specific treatments are available. In developing this form of AKI, activation of the renin-angiotensin system (RAS) has been proposed to play an important role. In this review, we discuss the role of RAS activation and its contribution to the pathophysiology of DGF following the different stages of the transplantation process, from procurement and ischemia to transplantation into the recipient and including data from experimental animal models. Deceased kidney donors, whether during cardiac or brain death, may experience activation of the RAS. That may be continued or further potentiated during procurement and organ preservation. Additional evidence suggests that during implantation of the kidney graft and reperfusion in the recipient, the RAS is activated and may likely remain activated, extrapolating from other forms of AKI where RAS overactivity is well documented. Of particular interest in this setting is the status of angiotensin-converting enzyme 2, a key RAS enzyme essential for the metabolism of angiotensin II and abundantly present in the apical border of the proximal tubules, which is the site of predominant injury in AKI and DGF. Interventions aimed at safely downregulating the RAS using suitable shorter forms of angiotensin-converting enzyme 2 could be a way to offer protection against DGF.

Reactive oxygen species (ROS) and inflammation are reported to have a fundamental role in the pathogenesis of ischemia-reperfusion (IR) injury, a leading cause of acute kidney injury. The present study investigated the role of pyruvate dehydrogenase kinase 4 (PDK4) in ROS production and inflammation following IR injury.

We used a streptozotocin-induced diabetic C57BL6/J mouse model, which was subjected to IR by clamping both renal pedicles. Cellular apoptosis and inflammatory markers were evaluated in NRK-52E cells and mouse primary tubular cells after hypoxia and reoxygenation using a hypoxia work station.

Following IR injury in diabetic mice, the expression of PDK4, rather than the other PDK isoforms, was induced with a marked increase in pyruvate dehydrogenase E1α (PDHE1α) phosphorylation. This was accompanied by a pronounced ROS activation, as well as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and monocyte chemoattractant protein-1 (MCP-1) production. Notably, sodium dichloroacetate (DCA) attenuated renal IR injury-induced apoptosis which can be attributed to reducing PDK4 expression and PDHE1α phosphorylation levels. DCA or shPdk4 treatment reduced oxidative stress and decreased TNF-α, IL-6, IL-1β, and MCP-1 production after IR or hypoxia-reoxygenation injury.

PDK4 inhibition alleviated renal injury with decreased ROS production and inflammation, supporting a critical role for PDK4 in IR mediated damage. This result indicates another potential target for reno-protection during IR injury; accordingly, the role of PDK4 inhibition needs to be comprehensively elucidated in terms of mitochondrial function during renal IR injury.

Renal ischemia-reperfusion (I/R) can be precipitated by multiple clinical situations that lead to impaired renal function and associated mortality. The resulting tubular cell damage is the outcome of complex disorders including, an inflammatory process with an overproduction of cytokines. Here, diacerein (DIA), an inhibitor of proinflammatory cytokine interleukin-1 beta (IL-1β), was investigated against renal I/R in rats. DIA was orally administrated (50 mg/kg/day) for ten days before bilateral ischemia for 45 min with subsequent 2 hr. reperfusion. Interestingly, DIA alleviated the renal dysfunction and histopathological damage in the renal tissues. Pretreatment with DIA corrected the oxidative imbalance by prevented reduction in antioxidant levels of GSH and SOD, while it decreased the elevation of the oxidative marker, MDA. In addition, DIA downregulated IL-1β and TNF-α expression in the renal tissues. Consequent to inhibition of the oxidative stress and inflammatory cascades, DIA inhibited the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK). Therefore, downstream targets for p38 MAPK were also inhibited via DIA which prevented further increases of inflammatory cytokines and the apoptotic marker, caspase-3. Collectively, this study revealed the renoprotective role of DIA for renal I/R and highlighted the role of p38 MAPK encountered in its therapeutic application in renal disease.

Acute kidney injury (AKI) is associated with immune cell activation and inflammation. However, the putative pathogenic mechanisms of this injury have not been thoroughly investigated. Natural killer (NK) cells play an important role in immune regulation; however, whether NK cells regulate AKI remains unclear. Cordyceps sinensis (CS), a modern Chinese patented medicine preparation, has been widely used in treating patients with chronic kidney disease (CKD) owing to its anti-inflammatory effects and maintenance of immune homeostasis. Whether 2'-deoxyadenosine, a major active component in CS, can ameliorate renal AKI by regulating immunity, particularly in NK cells, has not been reported. This study is the first to demonstrate how NK cells promote AKI by releasing perforin, interferon-gamma (IFN-γ) and other inflammatory factors in vivo and in vitro. Differential gene expression between AKI and normal tissues was assessed using bioinformatic analyses. Quantitative real-time PCR, western blotting, and immunohistochemical staining were used to detect target protein mRNA and protein expression. Levels of inflammatory factors were measured using enzyme-linked immunosorbent assay. We found the high doses of the 2'-deoxyadenosine treatment significantly alleviated FA-induced renal damage in vivo, and alleviated the NK cells of renal injury by activating the STING/IRF3 pathway to inhibit perforin release in vitro. The results showed that 2'-deoxyadenosine could mitigate AKI by downregulating the activity of NK cells (by decreasing the expressions of perforin and IFN-γ) and inhibiting the stimulator of interferon genes and phosphorylated IFN regulatory factor 3. This may provide valuable evidence supporting the clinical use of CS in treating patients with AKI.

Critical limb ischemia (CLI) is the advanced stage of peripheral arterial disease, which impairs blood flow to the extremities due to occlusion of arteries, in which patients suffer from ischemic pain at rest and gangrene or ulcers. It is frequently accompanied by major adverse cardiac events, resulting in exceedingly high mortality from a cardiac or cerebrovascular event in this population. Although there have been considerable amounts of novel and costly revascularization and wound dressing technology, mortality is still high. Therefore, the risk factors for such high mortality need to be addressed. This review aimed to summarize the potential risk factors for mortality in patients with CLI of the lower extremities. There are several such risk factors, including modifiable and nonmodifiable risk factors. This review further discusses some highlighted major modified risk factors, including renal failure, cardiovascular, and diabetes. The strategy of regular surveillance and modification of such risk factors in any patients with CLI should be developed.

The growing interest in nanomedicine over the last 20 years has carved out a research field called "nanocatalytic therapy," where catalytic reactions mediated by nanomaterials are employed to intervene in disease-critical biomolecular processes. Among many kinds of catalytic/enzyme-mimetic nanomaterials investigated thus far, ceria nanoparticles stand out from others owing to their unique scavenging properties against biologically noxious free radicals, including reactive oxygen species (ROS) and reactive nitrogen species (RNS), by exerting enzyme mimicry and nonenzymatic activities. Much effort has been made to utilize ceria nanoparticles as self-regenerating antioxidative and anti-inflammatory agents for various kinds of diseases, given the detrimental effects of ROS and RNS therein that need alleviation. In this context, this review is intended to provide an overview as to what makes ceria nanoparticles merit attention in disease therapy. The introductory part describes the characteristics of ceria nanoparticles as an oxygen-deficient metal oxide. The pathophysiological roles of ROS and RNS are then presented, as well as their scavenging mechanisms by ceria nanoparticles. Representative examples of recent ceria-nanoparticle-based therapeutics are summarized by categorization into organ and disease types, followed by the discussion on the remaining challenges and future research directions.

The relationships of social isolation and loneliness with acute kidney injury (AKI) risk remained uncertain. We aimed to investigate the associations of social isolation and loneliness with incident AKI.

450,868 participants without prior AKI were included from the UK Biobank. The social isolation index was constructed based on living alone, social contact, and participation in social activities. Loneliness was assessed by asking about "Do you often feel lonely?". The study outcome was incident AKI.

During a median follow-up of 12.0 years, 18,679 (4.1%) participants developed AKI, including 18,428 participants ascertained by hospital admission records with a median duration of hospitalization of 3 (25th-75th, 1-8) days. The hazard ratio for incident AKI for social isolation compared with no social isolation was 1.50 (95% CI: 1.44-1.55) after adjusting for age and race (minimally adjusted), and was 1.10 (95% CI: 1.06-1.14) after further adjusting for socioeconomic factors, health behaviors, biological and health-related factors, psychologic factors, and loneliness (fully adjusted). The minimally adjusted and fully adjusted hazard ratios for incident AKI for loneliness compared with no loneliness was 1.57 (95% CI: 1.52-1.62), and 1.10 (95% CI: 1.06-1.15), respectively. In the fully adjusted models, the highest risk of AKI was found in those with both social isolation and loneliness. Living alone and less social contact, rather than less participation in social activities, were significantly associated with a higher risk of incident AKI.

Both social isolation and loneliness were independently and significantly associated with a higher risk of incident AKI.

Renal fibrosis is increasingly recognized as a global public health problem. Acute kidney injury (AKI) and chronic kidney disease (CKD) both result in renal fibrosis. Oxidative stress and inflammation play central roles in progressive renal fibrosis. Oxidative stress and inflammation are closely linked and form a vicious cycle in which oxidative stress induces inflammation through various molecular mechanisms. Ample evidence has indicated that a hyperactive nuclear factor kappa B (NF-ƙB) signaling pathway plays a pivotal role in renal fibrosis. Hyperactive NF-ƙB causes the activation and recruitment of immune cells. Inflammation, in turn, triggers oxidative stress through the production of reactive oxygen species and nitrogen species by activating leukocytes and resident cells. These events mediate organ injury through apoptosis, necrosis, and fibrosis. Therefore, developing a strategy to target the NF-ƙB signaling pathway is important for the effective treatment of renal fibrosis. This Review summarizes the effect of the NF-ƙB signaling pathway on renal fibrosis in the context of AKI and CKD (immunoglobulin A nephropathy, membranous nephropathy, diabetic nephropathy, hypertensive nephropathy, and kidney transplantation). Therapies targeting the NF-ƙB signaling pathway, including natural products, are also discussed. In addition, NF-ƙB-dependent non-coding RNAs are involved in renal inflammation and fibrosis and are crucial targets in the development of effective treatments for kidney disease. This Review provides a clear pathophysiological rationale and specific concept-driven therapeutic strategy for the treatment of renal fibrosis by targeting the NF-ƙB signaling pathway.

Organ transplantation is characterized by a sequence of steps that involve operative trauma, organ preservation, and ischemia-reperfusion injury in the transplant recipient. During this process, the release of damage-associated molecular patterns (DAMPs) promotes the activation of innate immune cells via engagement of the toll-like receptor (TLR) system, the complement system, and coagulation cascade. Different classes of effector responses are then carried out by specialized populations of macrophages, dendritic cells, and T and B lymphocytes; these play a central role in the orchestration and regulation of the inflammatory response and modulation of the ensuing adaptive immune response to transplant allografts. Organ function and rejection of human allografts have traditionally been studied through the lens of adaptive immunity; however, an increasing body of work has provided a more comprehensive picture of the pivotal role of innate regulation of adaptive immune responses in transplant and the potential therapeutic implications. Herein we review literature that examines the repercussions of inflammatory injury to transplantable organs. We highlight novel concepts in the pathophysiology and mechanisms involved in innate control of adaptive immunity and rejection. Furthermore, we discuss existing evidence on novel therapies aimed at innate immunomodulation and how this could be harnessed in the transplant setting.

Kidney stones is one of the serious medical conditions affecting populations worldwide. So, we aimed in this study to investigate the protective effect of allium cepa administration against KSD.

24 adult male albino rats were assigned into 3 groups; group I: control group; group II: received ethylene glycol (EG) in the drinking water for 4 weeks; and group III received EG in the drinking water plus freshly prepared allium cepa extract (ACE) for 4 weeks. Renal function tests and urine analysis were done. Tissue oxidative stress markers (SOD and MDA) were assessed, and kidney expression of SIRT-1, Beclin, LC3, osteopontin, and Regucalcin were measured by RT-qPCR. Histopathological assessment and immunohistochemistry for Bax, Beclin-1 and TNF-α were performed.

There was a significant improved kidney function tests in the ACE received group compared to EG group (P < 0.001). The present study showed less stones formation and apoptosis with decreased osteopontin and autophagy genes expression in the ACE received group compared to EG group (P < 0.001). While, regucalcin and SIRT-1 genes showed higher expression in the former group than the later group (P < 0.001).

Alium Cepa extract administration has a significant protective effect against kidney stones formation.

Ischemic acute kidney injury (AKI) is a prevalent disorder among hospitalized patients worldwide. Astragaloside IV (AS-IV) has been shown to protect against ischemic AKI. However, the specific effects and mechanisms of AS-IV on alleviating kidney ischemia-reperfusion (I/R) injury remain unclear. The objective of this research was to elucidate the regulatory targets and mechanisms through which AS-IV protects kidney I/R injury. A combination of network pharmacology, molecular docking, molecular dynamics (MD) simulation, pharmacodynamic study and Western blot were employed to explore the underlying mechanisms. Network pharmacology revealed that ferroptosis was a potential mechanism of AS-IV against kidney I/R injury. Molecular docking and MD simulations demonstrated strong binding affinity between the GPX4/SLC7A11 and AS-IV. The experimental verification demonstrated that AS-IV improved cell proliferation, decreased the level of ROS and Fe2+, and increased the expressions of GPX4 and SLC7A11 as same as Ferrostatin-1 in OGD/R-injured HUVECs. In conclusion, AS-IV had a significant inhibition on ferroptosis in kidney I/R injury, providing a new perspective for drug development on kidney I/R injury. Definitely, further exploration in vivo is necessary to fully understand whether AS-IV alleviates kidney I/R injury through inhibiting endothelial ferroptosis.

Renal ischemia-reperfusion (I-R) injury is a complex pathophysiologic condition characterized by oxidative stress, inflammation and apoptosis. We investigated the potential renoprotective effect of nebivolol, a β1 adrenergic receptor blocker, against renal I-R injury. We focused on the role of nebivolol in activating p38 mitogen-activated protein kinase (MAPK) signaling, Akt (protein kinase B) and nuclear factor-κB (NFκB) transcription factors, which contribute to oxidative stress, inflammation and apoptosis during renal I-R. We divided 20 adult male Wistar albino rats into three experimental groups. Group 1 was a sham control in which only laparotomy was performed. Group 2 was the I-R group in which both kidneys were made ischemic for 45 min, then reperfused for 24 h. Group 3 was the I-R + nebivolol group in which 10 mg/kg nebivolol was administrated by gavage for 7 days before I-R. We measured Inflammation, oxidative stress and active caspase-3 as well as activation of p38 MAPK, Akt (protein kinase B) and NFκB transcription factor. Nebivolol significantly reduced oxidative stress and increased superoxide dismutase levels during renal I-R. We found that nebivolol significantly decreased interstitial inflammation, and TNF-α and interleukin-1β mRNA expression. Nebivolol significantly reduced active caspase-3 and kidney injury molecule-1 (KIM-1) expressions. Nebivolol also significantly decreased activation of p38 MAPK signaling and NFκB, and induced Akt activation during renal I-R. Our findings suggest that nebivolol may be useful for management of renal I-R injury.

ELABELA (ELA), also known as Toddler or Apela, is a novel endogenous ligand of the angiotensin receptor AT1-related receptor protein (APJ). ELA is highly expressed in human embryonic, cardiac, and renal tissues and involves various biological functions, such as embryonic development, blood circulation regulation, and maintaining body fluid homeostasis. ELA is also closely related to the occurrence and development of acute kidney injury, hypertensive kidney damage, diabetic nephropathy, renal tumors, and other diseases. Understanding the physiological role of ELA and its mechanism of action in kidney-related diseases would provide new targets and directions for the clinical treatment of kidney diseases.

Acute kidney injury (AKI) is often caused by ischemia-reperfusion injury (IRI). IRI significantly affects kidney metabolism, which elicits pro-inflammatory responses and kidney injury. The ischemia/reperfusion of the kidney is associated with transient high mitochondrial-derived reactive oxygen species (ROS) production rates. Excessive mitochondrial-derived ROS damages cellular components and, together with other pathogenic mechanisms, elicits a range of acute injury mechanisms that impair kidney function. Mitochondrial-derived ROS production also stimulates epithelial cell secretion of extracellular vesicles (EVs) containing RNAs, lipids, and proteins, suggesting that EVs are involved in AKI pathogenesis. This literature review focuses on how EV secretion is stimulated during ischemia/reperfusion and how cell-specific EVs and their molecular cargo may modify the IRI process. Moreover, critical pitfalls in the analysis of kidney epithelial-derived EVs are described. In particular, we will focus on how the release of kidney epithelial EVs is affected during tissue analyses and how this may confound data on cell-to-cell signaling. By increasing awareness of methodological pitfalls in renal EV research, the risk of false negatives can be mitigated. This will improve future EV data interpretation regarding EVs contribution to AKI pathogenesis and their potential as biomarkers or treatments for AKI.

There are several Amazonian plant species with potential pharmacological validation for the treatment of acute kidney injury, a condition in which the kidneys are unable to adequately filter the blood, resulting in the accumulation of toxins and waste in the body. Scientific production on plant compounds capable of preventing or attenuating acute kidney injury-caused by several factors, including ischemia, toxins, and inflammation-has shown promising results in animal models of acute kidney injury and some preliminary studies in humans. Despite the popular use of Amazonian plant species for kidney disorders, further pharmacological studies are needed to identify active compounds and subsequently conduct more complex preclinical trials. This article is a brief review of phytocompounds with potential nephroprotective effects against acute kidney injury (AKI). The classes of Amazonian plant compounds with significant biological activity most evident in the consulted literature were alkaloids, flavonoids, tannins, steroids, and terpenoids. An expressive phytochemical and pharmacological relevance of the studied species was identified, although with insufficiently explored potential, mainly in the face of AKI, a clinical condition with high morbidity and mortality.

The global increase in the incidence of kidney failure constitutes a major public health problem. Kidney disease is classified into acute and chronic: acute kidney injury (AKI) is associated with an abrupt decline in kidney function and chronic kidney disease (CKD) with chronic renal failure for more than three months. Although both kidney syndromes are multifactorial, inflammation and oxidative stress play major roles in the diversity of processes leading to these kidney malfunctions. Here, we reviewed various publications on medicinal plants with antioxidant and anti-inflammatory properties with the potential to treat and manage kidney-associated diseases in rodent models. Additionally, we conducted a meta-analysis to identify gene signatures and associated biological processes perturbed in human and mouse cells treated with antioxidants such as epigallocatechin gallate (EGCG), the active ingredient in green tea, and the mushroom Ganoderma lucidum (GL) and in kidney disease rodent models. We identified EGCG- and GL-regulated gene signatures linked to metabolism; inflammation (NRG1, E2F1, NFKB1 and JUN); ion signalling; transport; renal processes (SLC12A1 and LOX) and VEGF, ERBB and BDNF signalling. Medicinal plant extracts are proving to be effective for the prevention, management and treatment of kidney-associated diseases; however, more detailed characterisations of their targets are needed to enable more trust in their application in the management of kidney-associated diseases.

Acute kidney injury (AKI) caused by anti-tumor drugs, such as cisplatin, is a severe complication with no effective treatment currently, leading to the reduction or discontinuation of chemotherapy. Natural products or herbal medicines are gradually considered as promising agents against cisplatin-induced AKI with the advantages of multi-targeting, multi-effects, and less resistance. In this study, we investigated the effects of kaempferide, a natural flavonoid extracted from the rhizome of Kaempferia galanga, in experimental AKI models in vitro and in vivo. We first conducted pharmacokinetic study in mice and found a relative stable state of kaempferide with a small amount of conversion into kaempferol. We showed that both kaempferide (10 μM) and kaempferol (10 μM) significantly inhibited cisplatin-caused injuries in immortalized proximal tubule epithelial cell line HK-2. In AKI mice induced by injection of a single dose of cisplatin (15 mg/kg), oral administration of kaempferide (50 mg/kg) either before or after cisplatin injection markedly improved renal function, and ameliorated renal tissue damage. We demonstrated that kaempferide inhibited oxidative stress and induced autophagy in cisplatin-treated mice and HK-2 cells, thus increasing tubular cell viability and decreasing immune responses to attenuate the disease progression. In addition, treatment with kaempferide significantly ameliorated ischemia-reperfusion-induced renal injury in vitro and in vivo. We conclude that kaempferide is a promising natural product for treating various AKI. This study has great implications for promotion of its use in healthcare products, and help to break through the limited use of cisplatin in the clinic.

Introduction: Regardless of initiating cause, renal injury promotes a potent pro-inflammatory environment in the outer medulla and a concomitant sustained decrease in medullary blood flow (MBF). This decline in MBF is believed to be one of the critical events in the pathogenesis of acute kidney injury (AKI), yet the precise cellular mechanism underlying this are still to be fully elucidated. MBF is regulated by contractile pericyte cells that reside on the descending vasa recta (DVR) capillaries, which are the primary source of blood flow to the medulla. Methods: Using the rat and murine live kidney slice models, we investigated the acute effects of key medullary inflammatory mediators TNF-α, IL-1β, IL-33, IL-18, C3a and C5a on vasa recta pericytes, the effect of AT1-R blocker Losartan on pro-inflammatory mediator activity at vasa recta pericytes, and the effect of 4-hour sustained exposure on immunolabelled NG2+ pericytes. Results and discussion: Exposure of rat and mouse kidney slices to TNF-α, IL-18, IL-33, and C5a demonstrated a real-time pericyte-mediated constriction of DVR. When pro-inflammatory mediators were applied in the presence of Losartan the inflammatory mediator-mediated constriction that had previously been observed was significantly attenuated. When live kidney slices were exposed to inflammatory mediators for 4-h, we noted a significant reduction in the number of NG2+ positive pericytes along vasa recta capillaries in both rat and murine kidney slices. Data collected in this study demonstrate that inflammatory mediators can dysregulate pericytes to constrict DVR diameter and reduce the density of pericytes along vasa recta vessels, further diminishing the regulatory capacity of the capillary network. We postulate that preliminary findings here suggest pericytes play a role in AKI.

Surgery-induced renal ischemia and reperfusion (I/R) injury and nephrotoxic drugs like cisplatin can cause acute kidney injury (AKI), for which there is no effective therapy. Lipid accumulation is evident following AKI in renal tubules although the mechanisms and pathological effects are unclear. Here, we report that Ehmt2-encoded histone methyltransferase G9a is upregulated in patients and mouse kidneys after AKI. Renal tubular specific knockout of G9a (Ehmt2Ksp ) or pharmacological inhibition of G9a alleviates lipid accumulation associated with AKI. Mechanistically, G9a suppresses transcription of the lipolytic enzyme Ces1; moreover, G9a and farnesoid X receptor (FXR) competitively bind to the same promoter regions of Ces1. Ces1 is consistently observed to be downregulated in the kidney of AKI patients. Pharmacological inhibition of Ces1 increases lipid accumulation, exacerbates renal I/R-injury and eliminates the beneficial effects on AKI observed in Ehmt2Ksp mice. Furthermore, lipid-lowering atorvastatin and an FXR agonist alleviate AKI by activating Ces1 and reducing renal lipid accumulation. Together, our results reveal a G9a/FXR-Ces1 axis that affects the AKI outcome via regulating renal lipid accumulation.

Diabetes mellitus (DM) is the most common cause of chronic kidney disease, which leads to end-stage renal failure worldwide. Glomerular damage, renal arteriosclerosis, and atherosclerosis are the contributing factors in diabetic patients, leading to the progression of kidney damage. Diabetes is a distinct risk factor for acute kidney injury (AKI) and AKI is associated with faster advancement of renal disease in patients with diabetes. The long-term consequences of AKI include the development of end-stage renal disease, higher cardiovascular and cerebral events, poor quality of life, and high morbidity and mortality. In general, not many studies discussed extensively "AKI in DM." Moreover, articles addressing this topic are scarce. It is also important to know the cause of AKI in diabetic patients so that timely intervention and preventive strategies can be implemented to decrease kidney injury. Aim of this review article is to address the epidemiology of AKI, its risk factors, different pathophysiological mechanisms, how AKI differs between diabetic and nondiabetic patients and its preventive and therapeutic implications in diabetics. The increasing occurrence and prevalence of AKI and DM, as well as other pertinent issues, motivated us to address this topic.

Acute kidney injury (AKI) and diabetes mellitus (DM) are public health problems that cause a high socioeconomic burden worldwide. In recent years, the landscape of AKI etiology has shifted: Emerging evidence has demonstrated that DM is an independent risk factor for the onset of AKI, while an alternative perspective considers AKI as a bona fide complication of DM. Therefore, it is necessary to systematically characterize the features of AKI in DM. In this review, we summarized the epidemiology of AKI in DM. While focusing on circulation- and tissue-specific microenvironment changes after DM, we described the active cellular and molecular mechanisms of increased kidney susceptibility to AKI under DM stress. We also reviewed the current diagnostic and therapeutic strategies for AKI in DM recommended in the clinic. Updated recognition of the epidemiology, pathophysiology, diagnosis, and medications of AKI in DM is believed to reveal a path to mitigate the frequency of AKI and DM comorbidity that will ultimately improve the quality of life in DM patients.

Ischemia/reperfusion injury (IRI) is a common cause of kidney damage, characterized by oxidative stress and inflammation. In this study, we investigated the potential protective effects of IAXO-102, a chemical compound, on experimentally induced IRI in male rats. The bilateral renal IRI model was used, with 24 adult male rats randomly divided into four groups (N=6): sham group (laparotomy without IRI induction), control group (laparotomy plus bilateral IRI for 30 minutes followed by 2 hours of reperfusion), vehicle group (same as control but pre-injected with the vehicle), and treatment group (similar to control but pre-injected with IAXO-102). We measured several biomarkers involved in IRI pathophysiology using enzyme-linked immunosorbent assay (ELISA), including High mobility group box1 (HMGB1), nuclear factor kappa b-p65 (NF-κB p65), interleukin beta-1 (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), 8-isoprostane, Bcl-2 associated X protein (BAX), heat shock protein 27 (HSP27), and Bcl-2. Statistical analysis was performed using one-way ANOVA and Tukey post hoc tests. Our results showed that IAXO-102 significantly improved kidney function, reduced histological alterations, and decreased the inflammatory response (IL-1, IL-6, and TNF) caused by IRI. IAXO-102 also decreased apoptosis by reducing pro-apoptotic Bax and increasing anti-apoptotic Bcl-2 without impacting HSP27. In conclusion, our findings suggest that IAXO-102 had a significant protective effect against IRI damage in the kidneys.

Inflammation plays an important role in the development of acute kidney injury (AKI). However, there are few studies exploring the prognostic influence of C-reactive protein to albumin ratio (CAR) among AKI patients. In this study, we investigated whether CAR could be a useful marker to predict the mortality of AKI.

A total of 358 AKI patients were extracted from the Medical Information Mart for Intensive Care III (MIMIC III) database. C-reactive protein (CRP) and albumin were measured at ICU admission. The clinical outcome was 365-day mortality. Cox proportional hazards model and Kaplan-Meier survival analysis were conducted to evaluate the association between CAR and outcome.

Compared with patients in the survival group, nonsurvivors had higher CAR levels. The area under the receiver operating characteristic (ROC) curve of CAR was higher than that of CRP and albumin for mortality (0.64 vs. 0.63, 0.59, respectively). The cut-off point of CAR for mortality was 7.23. In Cox proportional-hazard regression analysis, CAR (hazards ratio (HR) =2.04, 95% confidence interval (CI) =1.47-2.85, p < 0.001 for higher CAR) and Simplified Acute Physiology Score II (HR = 1.02, 95%CI = 1.00-1.03, p = 0.004) were independent predictors of 365-day mortality.

Our study demonstrated that a higher level of CAR was associated with 365-day mortality in AKI patients.

As one kind of novel noncoding RNA, circular RNAs (circRNAs) are involved in different biological processes. Although growing evidences have supported the important role of circRNAs in renal diseases, the mechanism remains unclear in neonatal acute kidney injury (AKI). High-throughput sequencing analysis was used to investigate the expression of circRNAs between hypoxia-induced AKI neonates and controls. Bioinformatics analysis was conducted to predict the function of differentially expressed circRNAs. Finally, the differentially expressed circRNAs were screened and determined by quantitative real-time PCR (qPCR). (1) A total of 296 differentially expressed circRNAs were identified (Fold change >2 and p < 0.05). Of them, 184 circRNAs were markedly upregulated, and 112 were significantly downregulated in the AKI group. (2) The pathway analysis showed that ubiquitin-mediated proteolysis, renal cell carcinoma, Jak-STAT, and HIF-1 signaling pathways participated in AKI. (3) Top five upregulated and five downregulated circRNAs with higher fold changes were selected for qPCR validation. Hsa_circ_0008898 (Fold Change = 5.48, p = 0.0376) and hsa_circ_0005519 (Fold Change = 4.65, p = 0.0071) were significantly upregulated, while hsa_circ_0132279 (Fold Change = -4.47, p = 0.0008), hsa_circ_0112327 (Fold Change = -4.26, p = 0.0048), and hsa_circ_0017647 (Fold Change = -4.15, p = 0.0313) were significantly downregulated in asphyxia-induced AKI group compared with the control group. This study could contribute to future research on neonatal AKI and facilitate the identification of novel therapeutic targets.