Mincle receptor in macrophage and neutrophil contributes to the unresolved inflammation during the transition from acute kidney injury to chronic kidney disease.

Background: Recent studies have demonstrated a strong association between acute kidney injury (AKI) and chronic kidney disease (CKD), while the unresolved inflammation is believed to be a driving force for this chronic transition process. As a transmembrane pattern recognition receptor, Mincle (macrophage-inducible C-type lectin, Clec4e) was identified to participate in the early immune response after AKI. However, the impact of Mincle on the chronic transition of AKI remains largely unclear. Methods: We performed single-cell RNA sequencing (scRNA-seq) with the unilateral ischemia-reperfusion (UIR) murine model of AKI at days 1, 3, 14 and 28 after injury. Potential effects and mechanism of Mincle on renal inflammation and fibrosis were further validated in vivo utilizing Mincle knockout mice. Results: The dynamic expression of Mincle in macrophages and neutrophils throughout the transition from AKI to CKD was observed. For both cell types, Mincle expression was significantly up-regulated on day 1 following AKI, with a second rise observed on day 14. Notably, we identified distinct subclusters of Minclehigh neutrophils and Minclehigh macrophages that exhibited time-dependent influx with dual peaks characterized with remarkable pro-inflammatory and pro-fibrotic functions. Moreover, we identified that Minclehigh neutrophils represented an "aged" mature neutrophil subset derived from the "fresh" mature neutrophil cluster in kidney. Additionally, we observed a synergistic mechanism whereby Mincle-expressing macrophages and neutrophils sustained renal inflammation by tumor necrosis factor (TNF) production. Mincle-deficient mice exhibited reduced renal injury and fibrosis following AKI. Conclusion: The present findings have unveiled combined persistence of Minclehigh neutrophils and macrophages during AKI-to-CKD transition, contributing to unresolved inflammation followed by fibrosis via TNF-α as a central pro-inflammatory cytokine. Targeting Mincle may offer a novel therapeutic strategy for preventing the transition from AKI to CKD.

The Expression of Markers of Acute Kidney Injury Kim1 and NGAL after Administration of High Doses of Lithium Carbonate in Mice with Engrafted Skin Melanoma B16.

The expression of marker proteins of acute kidney injury after administration of high doses of lithium carbonate was assessed to evaluate the possibility of lithium use in neutron capture therapy. In mice with implanted skin melanoma B16, the expression of Kim1 (kidney injury molecule 1) and NGAL (neutrophil gelatinase-associated lipocalin) proteins in the kidneys was evaluated immunohistochemically 15, 30, 90, 180 min, and 7 days after peroral administration of lithium carbonate at single doses of 300 and 400 mg/kg. An increase in the expression of the studied proteins was found in 30 and 90 min after administration of 400 mg/kg lithium carbonate, however, 7 days after the drug administration, the expression returned to the level observed in the control group. It can be suggested that single administration of lithium carbonate in the studied doses effective for lithium neutron capture therapy will not significantly affect the renal function.

Acteoside and isoacteoside alleviate renal dysfunction and inflammation in lipopolysaccharide-induced acute kidney injuries through inhibition of NF-κB signaling pathway.

Acute kidney injury (AKI) is a sudden loss of renal function with a high mortality rate and inflammation is thought to be the underlying cause. The phenylpropanoid components acteoside (ACT) and isoacteoside (ISO), which were isolated from Cistanche deserticola Y.C.Ma, have been reported to have preventive effects against kidney disorders. This study aimed to investigate the anti-inflammatory properties and protective mechanisms of ACT and ISO. In this investigation, kidney function was assessed using a semi-automatic biochemical analyzer, histopathology was examined using Hematoxylin-Eosin staining and immunohistochemistry, and the concentration of inflammatory cytokines was assessed using an enzyme-linked immunosorbent assay (ELISA) test. In addition, using Western blot and q-PCR, the expression of proteins and genes connected to the NF-κB signaling pathway in mice with lipopolysaccharide (LPS)-induced AKI was found. The findings showed that under AKI intervention in LPS group, ACT group and ISO group, the expression of Rela (Rela gene is responsible for the expression of NFκB p65 protein) and Tlr4 mRNA was considerably elevated (P<0.01), which led to a significant improvement in the expression of MyD88, TLR4, Iκ-Bɑ and NF-κB p65 protein (P<0.001). The levels of Alb, Crea and BUN (P<0.001) increased along with the release of downstream inflammatory factors such as IL-1ß, IL-6, Cys-C, SOD1 and TNF-α (P<0.001). More importantly, the study showed that ISO had a more favorable impact on LPS-induced AKI mice than ACT. In conclusion, by inhibiting NF-κB signaling pathway, ACT and ISO could relieve renal failure and inflammation in AKI, offering a fresh possibility for the therapeutic management of the condition.

Berberine alleviated contrast-induced acute kidney injury by mitophagy-mediated NLRP3 inflammasome inactivation in a mice model.

The incidence of contrast-induced acute kidney injury (CI-AKI) has escalated to become the third most prevalent cause of hospital-acquired AKI, with a lack of efficacious interventions. Berberine (BBR) possesses diverse pharmacological effects and exhibits renoprotective properties; however, limited knowledge exists regarding its impact on CI-AKI. Therefore, our study aimed to investigate the protective effects and underlying mechanisms of BBR on CI-AKI in a mice model, focusing on the nucleotide-binding oligomerization domain-like pyrin domain-containing protein 3 (NLRP3) inflammasome and mitophagy. The CI-AKI mice model was established by administering NG-nitro-L-arginine methyl ester (L-NAME) (10 mg/kg), indomethacin (10 mg/kg), and iohexol (11 g/kg) following water deprivation. A pretreatment of 100 mg/kg of BBR was orally administered to the mice for two weeks. Renal injury markers, damage-associated molecular patterns (DAMPs), renal histopathology, mitochondrial morphology, autophagosomes, and potential mechanisms were investigated. BBR effectively reduced levels of renal injury biomarkers such as serum cystatin C, urea nitrogen, and creatinine, downregulated the protein level of kidney injury molecule 1 (KIM1), and mitigated renal histomorphological damage. Moreover, BBR reduced DAMPs, including high mobility group box-1 (HMGB1), heat shock protein 70 (HSP70), and uric acid (UA). It also alleviated oxidative stress and inflammatory factors such as monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1ß). Furthermore, the activation of NLRP3 inflammasome was attenuated in the BBR pretreatment group, as evidenced by both mRNA and protein levels. Electron microscopy and western blotting examination revealed that BBR mitigated mitochondrial damage and enhanced mitophagy. Additionally, BBR increased the P-AMPK/AMPK ratio. These findings indicated that BBR exerted a protective effect against CI-AKI by suppressing NLRP3 inflammasome activation and modulating mitophagy, providing a potential therapeutic strategy for its prevention.

Linagliptin ameliorates tacrolimus-induced renal injury: role of Nrf2/HO-1 and HIF-1α/CTGF/PAI-1.

BACKGROUND: Tacrolimus (TAC) is a frequently used immunosuppressive medication in organ transplantation. However, its nephrotoxic impact limits its long-term usage. This study aims to investigate the effect of linagliptin (Lina) on TAC-induced renal injury and its underlying mechanisms. METHODS AND RESULTS: Thirty-two Sprague Dawley rats were treated with TAC (1.5 mg/kg/day, subcutaneously) and/or Lina (5 mg/kg/day, orally) for 4 weeks. Histological examination was conducted, and serum and urinary biomarkers were measured to assess kidney function and integrity. Furthermore, ELISA, Western blot analysis and immunohistochemical assay were employed to determine signaling molecules of oxidative stress, profibrogenic, hypoxic, and apoptotic proteins. Tacrolimus caused renal dysfunction and histological deterioration evidenced by increased serum creatinine, blood urea nitrogen (BUN), urinary cystatin C, and decreased serum albumin as well as elevated tubular injury and interstitial fibrosis scores. Additionally, TAC significantly increased the expression of collagen type-1, alpha-smooth muscle actin (α-SMA), plasminogen activator inhibitor-1 (PAI-1), and transforming growth factor-beta1 (TGF-ß1) renal content. Moreover, TAC decreased the expression of nuclear factor erythroid-2-related factor2 (Nrf2), heme oxygenase 1 (HO-1), and mitochondrial superoxide dismutase (SOD2). In addition, TAC increased protein expression of hypoxia-inducible factor1-alpha (HIF-1α), connective tissue growth factor (CTGF), inducible nitric oxide synthase (iNOS), 8-hydroxy-2-deoxyguanosine (8-OHdG), as well as nitric oxide (NO), 4-hydroxynonenal, caspase-3 and Bax renal contents. Furthermore, TAC decreased Bcl-2 renal contents. The Lina administration markedly attenuated these alterations. CONCLUSION: Lina ameliorated TAC-induced kidney injury through modulation of oxidative stress, hypoxia, and apoptosis related proteins.

The Salutary Effects of Diminazene, Lisinopril or Valsartan on Cisplatin - Induced Acute Kidney Injury in Rats: A Comparative Study.

Nephrotoxicity as a cause of acute kidney injury (AKI) induced by cisplatin (CP), limits its usefulness as an anticancer agent. Diminazene, an angiotensin converting enzyme 2 activator, exhibited renoprotective properties on rat models of kidney diseases. This research aims to investigate the salutary effect of diminazene in comparison with lisinopril or valsartan in CP-induced AKI. The first and second groups of rats received oral vehicle (distilled water) for 9 days, and saline injection or intraperitoneal CP (6 mg/kg) on day 6, respectively. Third, fourth, and fifth groups received intraperitoneal injections of CP on day 6 and diminazene (15 mg/kg/day, orally), lisinopril (10 mg/kg/day, orally), or valsartan (30 mg/kg/day, orally), for 9 days, respectively. 24h after the last day of treatment, blood and kidneys were removed under anesthesia for biochemical and histopathological examination. Urine during the last 24 h before sacrificing the rats was also collected. CP significantly increased plasma urea, creatinine, neutrophil gelatinase-associated lipocalin, calcium, phosphorus, and uric acid. It also increased urinary albumin/creatinine ratio, N-Acetyl-beta-D-Glucosaminidase/creatinine ratio, and reduced creatinine clearance, as well the plasma concentrations of inflammatory cytokines [plasma tumor necrosis factor-alpha, and interleukin-1beta], and significantly reduced antioxidant indices [catalase, glutathione reductase , and superoxide dismutase]. Histopathologically, CP treatment caused necrosis of renal tubules, tubular casts, shrunken glomeruli, and increased renal fibrosis. Diminazine, lisinopril, and valsartan ameliorated CP-induced biochemical and histopathological changes to a similar extent. The salutary effect of the three drugs used is, at least partially, due to their anti-inflammatory and antioxidant effects. Keywords: Cisplatin, Diminazene, ACE2 activator, Lisinopril, Valsartan, Acute kidney injury.

ß-Hydroxybutyrate Protects Against Cisplatin-Induced Renal Damage via Regulating Ferroptosis.

Cisplatin is a particularly potent antineoplastic drug. However, its usefulness is restricted due to the induction of nephrotoxicity. More recent research has indicated that ß-hydroxybutyrate (ß-HB) protects against acute or chronic organ damage as an efficient healing agent. Nonetheless, the therapeutic mechanisms of ß-HB in acute kidney damage caused by chemotherapeutic drugs remain unclear. Our study developed a model of cisplatin-induced acute kidney injury (AKI), which involved the administration of a ketogenic diet or ß-HB. We analyzed blood urea nitrogen (BUN) and creatinine (Cr) levels in serum, and used western blotting and immunohistochemical staining to assess ferroptosis and the calcium/calmodulin-dependent kinase kinase 2 (Camkk2)/AMPK pathway. The mitochondrial morphology and function were examined. Additionally, we conducted in vivo and in vitro experiments using selective Camkk2 inhibitor or activator to investigate the protective mechanism of ß-HB on cisplatin-induced AKI. Exogenous or endogenous ß-HB effectively alleviated cisplatin-induced abnormally elevated levels of BUN and Cr and renal tubular necrosis in vivo. Additionally, ß-HB reduced ferroptosis biomarkers and increased the levels of anti-ferroptosis biomarkers in the kidney. ß-HB also improved mitochondrial morphology and function. Moreover, ß-HB significantly attenuated cisplatin-induced cell ferroptosis and damage in vitro. Furthermore, western blotting and immunohistochemical staining indicated that ß-HB may prevent kidney injury by regulating the Camkk2-AMPK pathway. The use of the Camkk2 inhibitor or activator verified the involvement of Camkk2 in the renal protection by ß-HB. This study provided evidence of the protective effects of ß-HB against cisplatin-induced nephrotoxicity and identified inhibited ferroptosis and Camkk2 as potential molecular mechanisms.

ß-HB protects against cisplatin-induced renal damage both in vivo and in vitro.Moreover, ß-HB is effective in attenuating cisplatin-induced lipid peroxidation and ferroptosis.The regulation of energy metabolism, as well as the treatment involving ß-HB, is associated with Camkk2.

Evaluating biomarkers for contrast-induced nephropathy following coronary interventions: an umbrella review on meta-analyses.

BACKGROUND: Contrast-induced nephropathy (CIN) is a form of acute kidney injury (AKI) occurring in patients undergoing cardiac catheterization, such as coronary angiography (CAG) or percutaneous coronary intervention (PCI). Although the conventional criterion for CIN detection involves a rise in creatinine levels within 72 h after contrast media injection, several limitations exist in this definition. Up to now, various meta-analyses have been undertaken to assess the accuracy of different biomarkers of CIN prediction. However, the existing body of research lacks a cohesive overview. To address this gap, a comprehensive umbrella review was necessary to consolidate and summarize the outcomes of prior meta-analyses. This umbrella study aimed to offer a current, evidence-based understanding of the prognostic value of biomarkers in predicting CIN. METHODS: A systematic search of international databases, including PubMed, Scopus, and Web of Science, from inception to December 12, 2023, was conducted to identify meta-analyses assessing biomarkers for CIN prediction. Our own meta-analysis was performed by extracting data from the included studies. Sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were assessed using Meta-Disc and CMA softwares. RESULTS: Twelve studies were ultimately included in the umbrella review. The results revealed that neutrophil gelatinase-associated lipocalin (NGAL) exhibited the highest area under the curve (AUC), followed by cystatin-C, urinary kidney injury molecule-1 (uKIM-1), and brain natriuretic peptide (BNP) with AUCs of 0.91, 0.89, 0.85, and 0.80, respectively. NGAL also demonstrated the highest positive likelihood ratio [effect size (ES): 6.02, 95% CI 3.86-9.40], followed by cystatin-C, uKIM-1, and BNP [ES: 4.35 (95% CI 2.85-6.65), 3.58 (95% CI 2.75-4.66), and 2.85 (95% CI 2.13-3.82), respectively]. uKIM-1 and cystatin-C had the lowest negative likelihood ratio, followed by NGAL and BNP [ES: 0.25 (95% CI 0.17-0.37), ES: 0.25 (95% CI 0.13-0.50), ES: 0.26 (95% CI 0.17-0.41), and ES: 0.39 (0.28-0.53) respectively]. NGAL emerged as the biomarker with the highest diagnostic odds ratio for CIN, followed by cystatin-C, uKIM-1, BNP, gamma-glutamyl transferase, hypoalbuminemia, contrast media volume to creatinine clearance ratio, preprocedural hyperglycemia, red cell distribution width (RDW), hyperuricemia, neutrophil-to-lymphocyte ratio, C-reactive protein (CRP), high-sensitivity CRP, and low hematocrit (P < 0.05). CONCLUSION: NGAL demonstrated superior diagnostic performance, exhibiting the highest AUC, positive likelihood ratio, and diagnostic odds ratio among biomarkers for CIN, followed by cystatin-C, and uKIM-1. These findings underscore the potential clinical utility of NGAL, cystatin-C and uKIM-1 in predicting and assessing CIN.

Obesity aggravates acute kidney injury resulting from ischemia and reperfusion in mice.

In critically ill patients, overweight and obesity are associated with acute respiratory distress syndrome and acute kidney injury (AKI). However, the effect of obesity on ischemia-reperfusion injury (IRI)-induced AKI is unknown. We hypothesized that obesity would aggravate renal IRI in mice. We fed mice a standard or high-fat diet for eight weeks. The mice were divided into four groups and submitted to sham surgery or IRI: obese, normal, normal + IRI, obese, and obese + IRI. All studies were performed 48 h after the procedures. Serum glucose, cholesterol, and creatinine clearance did not differ among the groups. Survival and urinary osmolality were lower in the obese + IRI group than in the normal + IRI group, whereas urinary neutrophil gelatinase-associated lipocalin levels, tubular injury scores, and caspase 3 expression were higher. Proliferating cell nuclear antigen expression was highest in the obese + IRI group, as were the levels of oxidative stress (urinary levels of thiobarbituric acid-reactive substances and renal heme oxygenase-1 protein expression), whereas renal Klotho protein expression was lowest in that group. Expression of glutathione peroxidase 4 and peroxiredoxin 6, proteins that induce lipid peroxidation, a hallmark of ferroptosis, was lower in the obese + IRI group. Notably, among the mice not induced to AKI, macrophage infiltration was greater in the obese group. In conclusion, greater oxidative stress and ferroptosis might aggravate IRI in obese individuals, and Klotho could be a therapeutic target in those with AKI.

Tissue Inhibitor Metalloproteinase-2·IGF-Binding Protein 7 for the Prediction of Acute Kidney Injury following Cardiac Surgery.

INTRODUCTION: Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common complication associated with increased morbidity and mortality. Tissue inhibitor metalloproteinase-2·insulin-like growth factor-binding protein 7 (TIMP-2·IGFBP7) determines tubular stress markers, which may occur prior to tubular damage. Previous studies on the use of TIMP-2·IGFBP7 for the prediction of CSA-AKI showed divergent results. Therefore, this study aimed to explore the predictive value of TIMP-2·IGFBP7 measurements for the early detection of acute kidney injury (AKI) and short-term adverse outcomes after cardiac surgery. METHODS: In the prospective cohort study, blood and urine samples were collected 6-12 h after cardiac surgery. Blood samples to monitor serum creatinine levels were additionally extracted from days 1 to 7. AKI was defined based on the KDIGO consensus guidelines. AKI within 7 days following surgery was the primary outcome. The initiation of renal replacement therapy, in intensive care unit mortality, and the combination of both were secondary outcomes. RESULTS: A total of 557 patients were enrolled; 134 (24.06%) of them developed AKI and 33 (5.9%) had moderate or severe AKI. AKI developed more frequently in elderly patients with diabetes or with higher baseline serum creatinine levels. Patients with AKI had higher EuroSCORE II, Cleveland Clinic Score, and simplified renal index (SRI) than those without AKI. Urinary TIMP-2·IGFBP7 was significantly higher in patients with AKI. The area under the curve was 0.66 in predicting all AKI and 0.70 in predicting stages 2 and 3 AKI. The resulting sensitivity and specificity were 44.0% and 83.9%, respectively, for a calculated threshold TIMP-2·IGFBP7 value of 0.265 (ng/mL)2/1,000. The TIMP-2·IGFBP7 values, SRI score, and age were significantly associated with AKI within 7 days postoperatively. A total of 33 patients reached the composite endpoint; the percentage of patients who reached the composite endpoint in the TIMP-2·IGFBP7 of >0.265 (ng/ml)2/1,000 group was significantly higher than that of ≤0.265 (ng/mL)2/1,000 group. CONCLUSIONS: Postoperative implementation of TIMP-2·IGFBP7 improved the prediction of CSA-AKI and may aid in identifying patients at risk of short-term adverse outcomes. We identified an ideal calculated cutoff value of 0.265 (ng/mL)2/1,000 for the prediction of CSA-AKI among all AKI patients.

Inhibition of Drp1-mediated mitochondrial fission improves contrast-induced acute kidney injury by targeting the mROS-TXNIP-NLRP3 inflammasome axis.

Acute kidney injury (AKI) is a critical complication known for their extremely high mortality rate and lack of effective clinical therapy. Disorders in mitochondrial dynamics possess a pivotal role in the occurrence and progression of contrast-induced nephropathy (CIN) by activating NLRP3 inflammasome. The activation of dynamin-related protein-1 (Drp1) can trigger mitochondrial dynamic disorders by regulating excessive mitochondrial fission. However, the precise role of Drp1 during CIN has not been clarified. In vivo experiments revealed that inhibiting Drp1 through Mdivi-1 (one selective inhibitor of Drp1) can significantly decrease the expression of p-Drp1 (Ser616), mitochondrial p-Drp1 (Ser616), mitochondrial Bax, mitochondrial reactive oxygen species (mROS), NLRP3, caspase-1, ASC, TNF-α, IL-1ß, interleukin (IL)-18, IL-6, creatinine (Cr), malondialdehyde (MDA), blood urea nitrogen (BUN), and KIM-1. Moreover, Mdivi-1 reduced kidney pathological injury and downregulated the interaction between NLRP3 and thioredoxin-interacting protein (TXNIP), which was accompanied by decreased interactions between TRX and TXNIP. This resulted in increasing superoxide dismutase (SOD) and CAT activity, TRX expression, up-regulating mitochondrial membrane potential, and augmenting ATP contents and p-Drp1 (Ser616) levels in the cytoplasm. However, it did not bring impact on the expression of p-Drp1 (Ser637) and TXNIP. Activating Drp-1though Acetaldehyde abrogated the effects of Mdivi-1. In addition, the results of in vitro studies employing siRNA-Drp1 and plasmid-Drp1 intervention in HK-2 cells treated with iohexol were consistent with the in vivo experiments. Our findings revealed inhibiting Drp1 phosphorylation at Ser616 could ameliorate iohexol -induced acute kidney injury though alleviating the activation of the TXNIP-NLRP3 inflammasome pathway.

Innovative insights: ITLN1 modulates renal injury in response to radiation.

Radiation-induced kidney injury is a common side effect of radiotherapy, as the pelvic region is in close proximity to the kidneys, posing a risk of inducing radiation-induced kidney injury when treating any pelvic malignancies with radiotherapy. This type of injury typically manifests as chronic kidney disease a few months after radiotherapy, with the potential to progress to end-stage renal disease. Radiation-induced damage involves various components of the kidney, including glomeruli, tubules, interstitium, and extracellular matrix. Therefore, investigating its molecular mechanisms is crucial. In this study, we extensively searched literature databases, selecting recent transcriptomic studies related to acute kidney injury (AKI) published in the past decade. We downloaded the raw RNA sequencing datasets GSE30718 and GSE66494 related to AKI from the GEO database and identified that intestinal-type lectin ITLN1 plays a significant role in regulating radiation-induced kidney injury in rats. Differential gene analysis was performed using chip data from the GEO database, and further bioinformatics analysis identified 13 genes that may be involved in regulating kidney injury, with ITLN1 being the most relevant to kidney damage, thus selected as the target gene for this study. Subsequently, a rat model of radiation-induced kidney injury was established for experimental validation, assessing kidney tissue morphology and injury extent through staining observation and immunohistochemical staining. The protective effect of ITLN1 on kidney function was evaluated by measuring changes in rat body weight and blood pressure, serum kidney injury markers, and kidney structure. The experimental results indicate that overexpression of ITLN1 can improve kidney function in rats with radiation-induced kidney injury by activating the Akt/GSK-3ß/Nrf2 signaling pathway, suppressing oxidative stress, cell apoptosis, inflammation, cellular senescence, and fibrosis. This study highlights the significant role of ITLN1 in regulating kidney injury, providing a novel target for future treatments of radiation-induced kidney injury.

The NLRP3 Inflammasome Is a Major Cause of Acute Renal Failure Induced by Polypeptide Antibiotics.

Drug-induced acute renal failure (ARF) is a public health concern that hinders optimal drug therapy. However, pathological mechanisms of drug-induced ARF remain to be elucidated. Here, we show that a pathological process of drug-induced ARF is mediated by proinflammatory cross-talk between kidney tubular cells and macrophages. Both polymyxin B and colistin, polypeptide antibiotics, frequently cause ARF, stimulated the ERK and NF-κB pathways in kidney tubular cells, and thereby upregulated M-CSF and MCP-1, leading to infiltration of macrophages into the kidneys. Thereafter, the kidney-infiltrated macrophages were exposed to polypeptide antibiotics, which initiated activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome. Interestingly, blockade of the NLRP3 activation clearly ameliorated the pathology of ARF induced by polypeptide antibiotics, suggesting that a combination of the distinct cellular responses to polypeptide antibiotics in kidney tubular cells and macrophages plays a key role in the pathogenesis of colistin-induced ARF. Thus, our results provide a concrete example of how drugs initiate ARF, which may give insight into the underlying pathological process of drug-induced ARF.

Protective effects of gallic acid against nickel-induced kidney injury: impact of antioxidants and transcription factor on the incidence of nephrotoxicity.

Nickel (Ni) is a common metal with a nephrotoxic effect, damaging the kidneys. This study investigated the mechanism by which gallic acid (GA) protects mice kidneys against renal damage induced by Nickel oxide nanoparticles (NiO-NPs). Forty male Swiss albino mice were randomly assigned into four groups, each consisting of ten mice (n = 10/group): Group I the control group, received no treatment; Group II, the GA group, was administrated GA at a dosage of 110 mg/kg/day body weight; Group III, the NiO-NPs group, received injection of NiO-NPs at a concentration of 20 mg/kg body weight for 10 consecutive days; Group IV, the GA + NiO-NPs group, underwent treatment with both GA and NiO-NPs. The results showed a significant increase in serum biochemical markers and a reduction in antioxidant activities. Moreover, levels of 8-hydroxy-2'-deoxyguanosine (8-OH-dG), phosphorylated nuclear factor kappa B (p65), and protein carbonyl (PC) were significantly elevated in group III compared with group I. Furthermore, the western blot analysis revealed significant high NF-κB p65 expression, immunohistochemistry of the NF-κB and caspase-1 expression levels were significantly increased in group III compared to group I. Additionally, the histopathological inspection of the kidney in group III exhibited a substantial increase in extensive necrosis features compared with group I. In contrast, the concomitant coadministration of GA and NiO-NPs in group IV showed significant biochemical, antioxidant activities, immunohistochemical and histopathological improvements compared with group III. Gallic acid has a protective role against kidney dysfunction and renal damage in Ni-nanoparticle toxicity.

SOX4 silencing alleviates renal injury in rats with acute renal failure by inhibiting the NF-κB signaling pathway and reducing apoptosis and oxidative stress.

Acute renal failure (ARF) is a huge threat to the lives of most patients in intensive care units, and there is currently no satisfactory treatment strategy. SRY-box transcription factor 4 (SOX4) plays a key role in the development of various diseases, but its effect on ARF is unknown. Therefore, this study aimed to explore the relationship between SOX4 and ARF. Blood samples were collected from 20 ARF patients and 20 healthy volunteers. We also established an ARF rat model by excising the right kidney and ligating the left renal artery, and SOX4 knockdown in ARF rats was achieved down by means of lentiviral infection. Subsequently, we used quantitative polymerase chain reaction and western bolt assays to detect the expression levels of SOX4 and nuclear factor-κB (NF-κB) signaling pathway-related proteins in human blood or rat renal tissue and hematoxylin and eosin and terminal deoxynucleotidyl transferase (TdT) 2'-deoxyuridine 5'-triphosphate (dUTP) nick-end labeling staining to observe the pathological changes and apoptosis of renal tissue. Enzyme-linked immunosorbent assay and biochemical kits were used to measure the levels of renal function-related indicators (blood urea nitrogen, creatinine, and neutrophil gelatinase-associated lipocalin) and inflammatory factors (interleukin [IL]-1ß, IL-6, and tumor necrosis factor-alpha), as well as changes in oxidative stress-related indicators (malondialdehyde [MDA], superoxide dismutase [SOD], and reactive oxygen species [ROS]) in rat serum. SOX4 expression levels in blood samples from ARF patients and renal tissue from ARF rats were significantly higher compared with those in healthy volunteers and control rats, respectively. ARF model rats displayed the typical ARF phenotype, while SOX4 silencing significantly improved pathological injury and apoptosis of renal tissue in ARF rats. Moreover, SOX4 silencing significantly inhibited increased levels of renal function-related indicators and inflammatory factors and reduced the level of excessive oxidative stress (MDA and ROS were upregulated, and SOD was downregulated) in ARF rats. SOX4 also reduced the activity of the NF-κB signaling pathway in ARF samples. Thus, SOX4 knockdown may reduce oxidative stress, the inflammatory response, and apoptosis by reducing the activity of the NF-κB signaling pathway, thereby improving renal injury in ARF rats.

P2X7 receptor knockout does not alter renal function or prevent angiotensin II-induced kidney injury in F344 rats.

P2X7 receptors mediate immune and endothelial cell responses to extracellular ATP. Acute pharmacological blockade increases renal blood flow and filtration rate, suggesting that receptor activation promotes tonic vasoconstriction. P2X7 expression is increased in kidney disease and blockade/knockout is renoprotective. We generated a P2X7 knockout rat on F344 background, hypothesising enhanced renal blood flow and protection from angiotensin-II-induced renal injury. CRISPR/Cas9 introduced an early stop codon into exon 2 of P2rx7, abolishing P2X7 protein in kidney and reducing P2rx7 mRNA abundance by ~ 60% in bone-marrow derived macrophages. The M1 polarisation response to lipopolysaccharide was unaffected but P2X7 receptor knockout suppressed ATP-induced IL-1ß release. In male knockout rats, acetylcholine-induced dilation of the renal artery ex vivo was diminished but not the response to nitroprusside. Renal function in male and female knockout rats was not different from wild-type. Finally, in male rats infused with angiotensin-II for 6 weeks, P2X7 knockout did not reduce albuminuria, tubular injury, renal macrophage accrual, and renal perivascular fibrosis. Contrary to our hypothesis, global P2X7 knockout had no impact on in vivo renal hemodynamics. Our study does not indicate a major role for P2X7 receptor activation in renal vascular injury.

Subcutaneous injection of adipose stromal cell-secretome improves renal function and reduces inflammation in established acute kidney injury.

BACKGROUND: Adipose stromal cells (ASC) are a form of mesenchymal stromal cells that elicit effects primarily via secreted factors, which may have advantages for the treatment of injury or disease. Several previous studies have demonstrated a protective role for MSC/ASC on mitigating acute kidney injury but whether ASC derived factors could hasten recovery from established injury has not been evaluated. METHODS: We generated a concentrated secretome (CS) of human ASC under well-defined conditions and evaluated its ability to improve the recovery of renal function in a preclinical model of acute kidney injury (AKI) in rats. 24 h following bilateral ischemia/reperfusion (I/R), rats were randomized following determination of plasma creatinine into groups receiving vehicle -control or ASC-CS treatment by subcutaneous injection (2 mg protein/kg) and monitored for evaluation of renal function, structure and inflammation. RESULTS: Renal function, assessed by plasma creatinine levels, recovered faster in ASC-CS treated rats vs vehicle. The most prominent difference between the ASC-CS treated vs vehicle was observed in rats with the most severe degree of initial injury (Pcr > 3.0 mg/dl 24 h post I/R), whereas rats with less severe injury (Pcr < 2.9 mg/dl) recovered quickly regardless of treatment. The quicker recovery of ASC-treated rats with severe injury was associated with less tissue damage, inflammation, and lower plasma angiopoietin 2. In vitro, ASC-CS attenuated the activation of the Th17 phenotype in lymphocytes isolated from injured kidneys. CONCLUSIONS: Taken together, these data suggest that ASC-CS represents a potent therapeutic option to improve established AKI.

Hazel Leaf Polyphenol Extract Alleviated Cisplatin-Induced Acute Kidney Injury by Reducing Ferroptosis through Inhibiting Hippo Signaling.

Derived from hazelnuts, hazel leaf has been utilized in traditional folk medicine for centuries in countries such as Portugal, Sweden, and Iran. In our previous investigations, we conducted a preliminary assessment of the hazel leaf polyphenol extract (referred to as ZP) and identified nine compounds, such as kaempferol and chlorogenic acid, in its composition. ZP has shown promising properties as an antioxidant and anti-inflammatory agent. Our research has revealed that ZP has protective effects against cisplatin-induced acute kidney injury (AKI). We conducted a comprehensive examination of both the pathological and ultrastructural aspects and found that ZP effectively ameliorated renal tissue lesions and mitigated mitochondrial damage. Moreover, ZP significantly suppressed malondialdehyde levels while increasing glutathione and catalase concentrations in the kidneys of AKI-induced mice. ZP decreased the number of apoptotic cells and decreased pro-apoptotic protein expression in the kidneys of mice and human renal tubular epithelial cells (HK-2). Furthermore, treatment with ZP increased the levels of proteins marking anti-ferroptosis, such as GPX4, FTH1, and FSP1, in experiments both in vivo and in vitro. We elucidated the underlying mechanisms of ZP's actions, revealing its inhibitory effect on Yap phosphorylation and its regulation of Lats expression, which exert a protective influence on the kidneys. Furthermore, we found that inhibiting the Hippo pathway compromised ZP's nephroprotective effects in both in vitro and in vivo studies. In summary, this research shows that ZP exhibits renoprotective properties, effectively reducing oxidative damage, apoptosis, and ferroptosis in the kidneys by targeting the Hippo pathway.

PDCD4-induced oxidative stress through FGR/NF-κB axis in rectal cancer radiotherapy-induced AKI.

This study aimed to investigate the molecular mechanism of the effect of PDCD4 on radiotherapy-induced acute kidney injury (AKI) in rectal cancer through the regulation of FGR/NF-κB signaling. Differentially expressed genes were identified using Gene Expression Omnibus (GEO) datasets (GSE90627 for rectal cancer and GSE145085 for AKI) and R software. The human renal tubular epithelial cell line, HK-2, was used to establish an in vitro model of radiotherapy-induced AKI. RT-qPCR and western blotting were used to detect gene and protein expression levels, respectively. Cell proliferation and apoptosis were assessed using the CCK-8 assay and flow cytometry, respectively. The malondialdehyde and superoxide dismutase levels in the cell culture supernatants were determined. Additionally, an in vivo AKI model was established using BALB/c mice, and kidney tissue morphology, expression of the renal injury molecule KIM-1, apoptosis of renal tubular cells, and TAS and TOS in serum were evaluated. Bioinformatics analysis revealed the upregulated expression of PDCD4 in AKI. In vitro experiments demonstrated that PDCD4 induced apoptosis in renal tubular cells by promoting FGR expression, which activated the NF-κB signaling pathway and triggered an oxidative stress response. In vivo animal experiments confirmed that PDCD4 promoted oxidative stress response and radiotherapy-induced AKI through the activation of the FGR/NF-κB signaling pathway. Silencing PDCD4 attenuated radiotherapy-induced AKI. Our findings suggest that PDCD4 may induce radiotherapy-induced AKI in rectal cancer by promoting FGR expression, activating the NF-κB signaling pathway, and triggering an oxidative stress response.

The SP1/SIRT1/ACLY signaling axis mediates fatty acid oxidation in renal ischemia-reperfusion-induced renal fibrosis.

BACKGROUND: Renal ischemia-reperfusion is the primary cause of acute kidney injury (AKI). Clinically, most patients who experience ischemia-reperfusion injury eventually progress gradually to renal fibrosis and chronic kidney disease (CKD). However, the underlying mechanism for AKI to CKD transition remain absent. Our study demonstrated that the downregulation of sirtuin 1 (Sirt1)-mediated fatty acid oxidation (FAO) facilitates IRI-induced renal fibrosis. METHODS: The IRI animal model was established, and ribonucleic acid (RNA) sequencing was used to explore potential differentially expressed genes (DEGs) and pathways. The SIRT1 knockout mice were generated, and a recombinant adeno-associated virus that overexpresses SIRT1 was injected into mice to explore the function of SIRT1 in renal fibrosis induced by renal IRI. In vitro, hypoxia/reoxygenation (H/R) was used to establish the classical model of renal IRI and overexpression or knockdown of SIRT1 to investigate the SIRT1 function through lentiviral plasmids. The underlying molecular mechanism was explored through RNA sequencing, bioinformatics analysis, and chromatin immunoprecipitation assay. RESULTS: RNA sequencing analysis and western blot demonstrated that the expression of SIRT1 was significantly decreased in IRI mice. Overexpression of SIRT1 improved renal function and reduced lipid deposition and renal fibrosis. On the contrary, knockout of SIRT1 aggravated kidney injury and renal fibrosis. RNA sequencing, bioinformatics analysis, and chromatin immunoprecipitation assay mechanistically revealed that SIRT1 impairs the acetylation of histone H3K27 on the promoter region of ACLY, thereby impeding FAO activity and promoting renal fibrosis. Additionally, SP1 regulated FAO by directly modulating SIRT1 expression. CONCLUSION: Our findings highlight that downregulation of SIRT1-modulated FAO facilitated by the SP1/SIRT1/ACLY axis in the kidney increases IRI, suggesting SIRT1 to be a potential therapeutic target for renal fibrosis induced by renal IRI.