Reduced Kidney Injury Research Articles

Downregulation of ARNTL in renal tubules of diabetic db/db mice reduces kidney injury by inhibiting ferroptosis

BackgroundThe prevalence of ferroptosis in diabetic kidney tubules has been documented, yet the underlying mechanism remains elusive. The aim of this study was to ascertain the pivotal gene linked to ferroptosis and establish a novel target for the prevention and management of diabetic kidney disease (DKD). MethodsTranscriptomics data (GSE184836) from DKD mice (C57BLKS/J) were retrieved from the GEO database and intersected with ferroptosis-related genes from FerrDb. Then, differentially expressed genes associated with ferroptosis in the glomeruli and tubules were screened. Gene ontology analysis and protein-protein interaction network construction were used to identify key genes. Western blotting and real-time quantitative polymerase chain reaction were employed to validate the expression in the same model. Aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL) expression in patients and mice with DKD was assessed using immunohistochemistry staining. ARNTL knockdown in C57BLKS/J mice was established and plasma malonaldehyde, superoxide dismutase, and renal pathology were analyzed. The efficacy of ARNTL knockdown was evaluated using proteomics analysis. Mitochondrial morphology was observed using transmission electron microscopy. ResultsARNTL was screened by bioinformatics analysis and its overexpression verified in patients and mice with DKD. ARNTL knockdown reduced oxidative stress in plasma. Kidney proteomics revealed that ferroptosis was inhibited. The reduction of the classic alteration in mitochondrial morphology associated with ferroptosis was also observed. Gene set enrichment analysis demonstrated that the downregulation of the TGFβ pathway coincided with a decrease in collagen protein and TGFβ1 levels. ConclusionsThe ferroptosis-associated gene ARNTL is a potential target for treating DKD.

Febuxostat alleviates Arsenic Trioxide-Induced renal injury in Rats: Insights on the crosstalk between NLRP3/TLR4, Sirt-1/NF-κB/TGF-β signaling Pathways, and miR-23b-3p, miR-181a-5b expression

Febuxostat (FBX), a xanthine oxidase inhibitor, is known to improve renal function and can show promise as a therapeutic agent for preventing drug-induced nephrotoxicity. This study aimed to explore the protective effect of FBX in preventing renal damage caused by arsenic trioxide (ATO) toxicity and uncover the underlying mechanisms. The researchers examined how FBX (10 mg/kg, orally) affected ATO-induced kidney injury (5 mg/kg, intraperitoneally) in rats. Kidney function and toxicity parameters in serum and oxidative stress biomarkers and inflammatory cytokine levels in renal tissue were measured. H&E staining was used to detect histopathological changes in the kidney. Network the molecular mechanisms of FBX in improving kidney injury were investigated using Western blotting and PCR techniques. The findings showed that FBX improved kidney function by inhibiting the pathological changes seen in H&E staining, decreasing levels of probed kidney function and toxicity measures in serum and tissue, and exhibiting antioxidant and anti-inflammatory effects. FBX decreased MDA, MPO, TNF-α, IL-1β, IL-6, COX-II, and NADPH oxidase levels, while increased GSH, GPx, SOD, and IL-10 levels. FBX also reduced the expression of NLRP3, ASC, TLR4, and micro-RNA 181a-5b while increased the expression of IKBα, Sirt-1, and micro-RNA 23b-3p, according to Western blotting and PCR results. In conclusion, FBX can play a vital role in reducing kidney injury in cases of ATO-induced nephrotoxicity, though more clinical research needs to be conducted.

Liensinine pretreatment reduces inflammation, oxidative stress, apoptosis, and autophagy to alleviate sepsis acute kidney injury.

Liensinine is mainly derived from alkaloids extracted and isolated from lotus seeds (Nelumbo nucifera Gaertn). It possesses anti-inflammatory, and antioxidant, according to contemporary pharmacological investigations. However, the effects and therapeutic mechanisms of liensinine on acute kidney injury (AKI) models of sepsis are unclear. To gain insight into these mechanisms, we established a sepsis kidney injury model by LPS injection of mice treated with liensinine, and stimulation of HK-2 with LPS in vitro and treated with liensinine and inhibitors of p38 MAPK, JNK MAPK. We first found that liensinine significantly reduced kidney injury in sepsis mice, while suppressing excessive inflammatory responses, restoring renal oxidative stress-related biomarkers, reducing increased apoptosis in TUNEL-positive cells and excessive autophagy, and that this process was accompanied by an increase in JNK/ p38-ATF 2 axis. In vitro experiments further demonstrated that lensinine reduced the expression of KIM-1, NGAL, inhibited pro- and anti-inflammatory secretion disorders, regulated the activation of the JNK/p38-ATF 2 axis, and reduced the accumulation of ROS, as well as the reduction of apoptotic cells detected by flow cytometry, and that this process played the same role as that of p38 MAPK, JNK MAPK inhibitors. We speculate that liensinine and p38 MAPK, JNK MAPK inhibitors may act on the same targets and could be involved in the mechanism of alleviating sepsis kidney injury in part through modulation of the JNK/p38-ATF 2 axis. Our study demonstrates that lensinine is a potential drug and thus provides a potential avenue for the treatment of AKI.

Normothermic Perfusion: A Game-Changer For Kidney Transplantation?

Respected Madam, Organ transplantation has revolutionized the field of medicine. Kidney transplant, in particular, is of significant importance in Pakistan as there is an estimated prevalence rate of patients with end-stage renal disease (ESRD) of 100 per million population. The annual transplant rate is only about 8 to 10 cases per million.1,2 Due to this shortage in organ transplants, over 15,0000 people lose their lives each year due to end-stage organ failure, among which 15000 are patients with end-stage kidney failure. These numbers can be reduced greatly if the number of kidneys available is increased.3 As the number of organs available for a kidney transplant is limited in Pakistan owing to strict regulations to end transplant tourism, it is crucial to increase the viability of the organs available to ensure the success and survival of patients suffering from ESRD.4 An exciting finding was revealed by Kidney Research UK, where 100 kidneys could potentially be saved for transplant each year after being retrieved from donors in the UK via normothermic perfusion, This technique has shown promising results in numerous research.5 As evident from the name, in this technique, oxygen is provided to organs during preservation to allow aerobic metabolism. In a review conducted by Franka Messner et al, it was concluded that this technology may be used as an ex-vivo organ assessment and treatment platform. During renal NMP, mesenchymal stromal/stem cells, multipotent adult progenitor cells, and microRNA have been used in studies, and preliminary data shows that these therapies do indeed reduce kidney injury and inflammatory response. Furthermore, in comparison to any cold preservation approach, normothermic ex vivo kidney perfusion (NEVKP) revealed a considerable reduction in preservation harm in a study conducted by Laura I Mazilescu et al.6 As the demand for kidney transplants increases in Pakistan, normothermic perfusion can be studied further to provide an efficient technique for the preservation of organs. By ensuring the better viability of the available organs, we can perhaps help to increase the chances of survival of patients suffering from ESRD since we already face a shortage in the number of organs available for transplantation.

Zileuton ameliorates aminoglycoside and polymyxin-associated acute kidney injury in an animal model.

Aminoglycosides and polymyxins are antibiotics with in vitro activity against MDR Gram-negative bacteria. However, their clinical use is hindered by dose-limiting nephrotoxicity. The objective of this project was to determine if zileuton can reduce nephrotoxicity associated with amikacin and polymyxin B in a rat model of acute kidney injury. Sprague Dawley rats (n = 10, both genders) were administered either amikacin (300 mg/kg) or polymyxin B (20 mg/kg) daily for 10 days. Zileuton (4 and 10 mg/kg) was delivered intraperitoneally 15 min before antibiotic administration. Blood samples were collected at baseline and daily to determine serum creatinine concentration. Nephrotoxicity was defined as a ≥2× elevation of baseline serum creatinine. Time-to-event analysis and log rank test were used to compare the onset of nephrotoxicity in different cohorts. Histopathological analysis was also conducted to characterize the extent of kidney injury. Animals receiving amikacin or polymyxin B alone had nephrotoxicity rates of 90% and 100%, respectively. The overall rate was reduced to 30% in animals receiving adjuvant zileuton. The onset of nephrotoxicity associated with amikacin and polymyxin B was also significantly delayed by zileuton at 4 and 10 mg/kg, respectively. Histopathology confirmed reduced kidney injury in animals receiving amikacin concomitant with zileuton. Our pilot data suggest that zileuton has the potential to attenuate nephrotoxicity associated with last-line antibiotics. This would allow these antibiotics to treat MDR Gram-negative bacterial infections optimally without dose-limiting constraints. Further studies are warranted to optimize drug delivery and dosing in humans.

Effects of photobiomodulation and caffeine treatment on acute kidney injury in a hypoxic ischemic neonatal rat model.

Hypoxic ischemic encephalopathy (HIE) occurs in 2-5/1000 births, with acute kidney injury (AKI) occurring in 40%. AKI increases morbidity and mortality. Caffeine, an adenosine receptor antagonist, and photobiomodulation (PBM), working on cytochrome c oxidase, are potential treatments for AKI. To examine effects of caffeine and PBM on AKI in rats, Day 7 pups underwent a HIE intervention (Modified Rice-Vannucci model) replicating pathology observed in humans. Caffeine was administered for 3 days and/or PBM for 5 days following HIE. Weights and urine for biomarkers (NGAL, albumin, KIM-1, osteopontin) were collected prior to HIE, daily post intervention and at sacrifice. Both treatments reduced kidney injury seen on electron microscopy, but not when combined. HIE elevated urinary NGAL and albumin on Days 1-3 post-HIE, before returning to control levels. This elevation was significantly reduced by PBM or caffeine. KIM-1 was significantly elevated for 7 days post-HIE and was reduced by both treatments. Osteopontin was not altered by HIE or the treatments. Treatments, individually but not in combination, improved HIE-induced reductions in the enzymatic activity of mitochondrial complexes II-III. PBM and caffeine also improved weight gain. PBM and caffeine reduces AKI diagnosed by urinary biomarkers and confirmed by EM findings.

#3259 ARTEMIS: A PHASE 3 STUDY OF RAVULIZUMAB TO PROTECT PATIENTS WITH CKD UNDERGOING CARDIAC SURGERY FROM AKI AND SUBSEQUENT MAJOR ADVERSE KIDNEY EVENTS

Abstract Background and Aims In patients undergoing cardiac surgery with cardiopulmonary bypass (CPB), pre-existing chronic kidney disease (CKD) confers a substantial risk for poor outcomes, including the development of cardiac surgery-associated acute kidney injury (CSA-AKI). CSA-AKI occurs in ≥50% of patients with CKD undergoing cardiac surgery with CPB vs ∼20–25% of patients without CKD1,2. The risk of subsequent Major Adverse Kidney Events (MAKE; a composite of sustained kidney dysfunction, initiation of dialysis, and death) is also elevated in patients with CKD. Causes of CSA-AKI are multifactorial and complex, and may include inflammation, oxidative stress, renal congestion, and ischaemic injury (such as ischaemic-reperfusion injury [IRI]). IRI is a common cause of AKI and typically results from early hypoperfusion while on bypass, followed by kidney injury upon reperfusion. There are currently no approved therapies that reduce the risk of AKI and associated poor outcomes after cardiac surgery with CPB3. Preclinical and clinical studies suggest that damage and inflammation caused by IRI and CPB is amplified by complement activation3; early treatment with C5 inhibitors, especially before onset of ischaemia, may lower the risk of damage. Method ARTEMIS is a Phase 3, randomised, double-blind, placebo-controlled, multicentre study of ravulizumab in adults with CKD and stable cardiac disease undergoing non-emergent sternotomy with CPB, to reduce the risk of post-operative AKI and subsequent MAKE 90 days post-surgery. Key inclusion and exclusion criteria can be found in Figure 1 and a study schematic in Figure 2. Briefly, the study consists of an up to 28-day screening period, randomisation and dosing 1–7 days prior to surgery with CPB (Day 1), a 90-day primary evaluation period post-CPB, and a survival follow-up at day 365 post-CPB. Approximately 736 participants will be randomised 1:1 to receive a single weight-based dose of ravulizumab or placebo; randomisation will be based on baseline CKD stage (3A, 3B, 4) and surgery type (mitral valve replacement or combined procedures vs other single procedures). The primary objective of this study is to assess the efficacy of ravulizumab in reducing the risk of MAKE90, defined as meeting ≥1 of the following by day 90 post-CPB: ≥25% sustained decrease from baseline in estimated glomerular filtration rate (calculated using the Chronic Kidney Disease Epidemiology Collaboration equation, based on serum Cystatin C); initiation of renal replacement therapy; death from any cause. The safety of ravulizumab in participants with CKD undergoing non-emergent CPB will also be evaluated. Other secondary objectives include assessment of ravulizumab efficacy for reducing AKI (based on serum creatinine) and MAKE risk at earlier timepoints following CPB, alongside any effects it may have on healthcare resource utilisation and health-related quality of life – as well as treatment immunogenicity – in participants with CKD undergoing non-emergent CPB. Results The final analysis will be conducted when all participants have completed the primary evaluation period. Conclusion The aim of this study is to assess whether terminal complement inhibition with ravulizumab is safe and effective in reducing kidney injury and improving outcomes in patients with CKD undergoing cardiac surgery with CPB.

The roles of heme oxygenase-1 in renal disease.

Heme oxygenase (HO), a heat shock protein containing hemoglobin, is an important enzyme in heme catabolism. It is involved in cell homeostasis and has anti-inflammatory, antioxidant, anti-apoptosis, immunomodulation, and other functions. It is expressed at a modest level in most normal tissues. When the body suffers from ischemia hypoxia, injury, toxins, and other nociceptive stimuli, the expression increases, which can transform the oxidative microenvironment into an antioxidant environment to promote tissue recovery from damage. In recent years, research has continued to verify its value in a variety of human bodily systems. It is also regarded as a key target for the treatment of numerous disorders. With the advancement of studies, its significance in renal disease has gained increasing attention. It is thought to have a significant protective function in preventing acute kidney injury and delaying the progression of chronic renal diseases. Its protective mechanisms include anti-inflammatory, antioxidant, cell cycle regulation, apoptosis inhibition, hemodynamic regulation, and other aspects, which have been demonstrated in diverse animal models. Furthermore, as a protective factor, its potential therapeutic efficacy in renal disease has recently become a hot area of research. Although a large number of preclinical trials have confirmed its therapeutic potential in reducing kidney injury, due to the problems and side effects of HO-1 induction therapy, its efficacy and safety in clinical application need to be further explored. In this review, we summarize the current state of research on the mechanism, location, and treatment of HO and its relationship with various renal diseases.

Diacylated anthocyanins from purple sweet potato (Ipomoeabatatas L.) attenuate hyperglycemia and hyperuricemia in mice induced by a high-fructose/high-fat diet.

Studies have shown that targeting xanthine oxidase (XO) can be a feasible treatment for fructose-induced hyperuricemia and hyperglycemia. This study aimed to evaluate the dual regulatory effects and molecular mechanisms of diacylated anthocyanins from purple sweet potato (diacylated AF-PSPs) on hyperglycemia and hyperuricemia induced by a high-fructose/high-fat diet. The body weight, organ index, serum biochemical indexes, and liver antioxidant indexes of mice were measured, and the kidneys were observed in pathological sections. The relative expression levels of messenger RNAs (mRNAs) of fructose metabolism pathway enzymes in kidney were detected by fluorescent real-time quantitative polymerase chain (qPCR) reaction technique, and the expression of renal transporter protein and inflammatory factor pathway protein was determined by immunohistochemistry (IHC) technique. Results showed that diacylated AF-PSPs alleviated hyperuricemia in mice, and that this effect might be related to the regulation of liver XO activity, lipid accumulation, and relevant renal transporters. Diacylated AF-PSPs reduced body weight and relieved lipid metabolism disorder, liver lipid accumulation, and liver oxidative stress, thereby enhancing insulin utilization and sensitivity, lowering blood sugar, and reducing hyperglycemia in mice. Also, diacylated AF-PSPs restored mRNA levels related to renal fructose metabolism, and reduced kidney injury and inflammation. This study provided experimental evidence for the mechanisms of dual regulation of blood glucose and uric acid (UA) by diacylated AF-PSPs and their utilization as functional foods in the management of metabolic syndrome.

Immune Checkpoint Molecule TIGIT Regulates Kidney T Cell Functions and Contributes to AKI.

T cells mediate pathogenic and reparative processes during AKI, but the exact mechanisms regulating kidney T cell functions are unclear. This study identified upregulation of the novel immune checkpoint molecule, TIGIT, on mouse and human kidney T cells after AKI. TIGIT-expressing kidney T cells produced proinflammatory cytokines and had effector (EM) and central memory (CM) phenotypes. TIGIT-deficient mice had protection from both ischemic and nephrotoxic AKI. Single-cell RNA sequencing led to the discovery of possible downstream targets of TIGIT. TIGIT mediates AKI pathophysiology, is a promising novel target for AKI therapy, and is being increasingly studied in human cancer therapy trials. T cells play pathogenic and reparative roles during AKI. However, mechanisms regulating T cell responses are relatively unknown. We investigated the roles of the novel immune checkpoint molecule T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) in kidney T cells and AKI outcomes. TIGIT expression and functional effects were evaluated in mouse kidney T cells using RNA sequencing (RNA-Seq) and flow cytometry. TIGIT effect on AKI outcomes was studied with TIGIT knockout (TIGIT-KO) mice in ischemia reperfusion (IR) and cisplatin AKI models. Human kidney T cells from nephrectomy samples and single cell RNA sequencing (scRNA-Seq) data from the Kidney Precision Medicine Project were used to assess TIGIT's role in humans. RNA-Seq and flow cytometry analysis of mouse kidney CD4+ T cells revealed increased expression of TIGIT after IR injury. Ischemic injury also increased TIGIT expression in human kidney T cells, and TIGIT expression was restricted to T/natural killer cell subsets in patients with AKI. TIGIT-expressing kidney T cells in wild type (WT) mice had an effector/central memory phenotype and proinflammatory profile at baseline and post-IR. Kidney regulatory T cells were predominantly TIGIT+ and significantly reduced post-IR. TIGIT-KO mice had significantly reduced kidney injury after IR and nephrotoxic injury compared with WT mice. scRNA-Seq analysis showed enrichment of genes related to oxidative phosphorylation and mTORC1 signaling in Th17 cells from TIGIT-KO mice. TIGIT expression increases in mouse and human kidney T cells during AKI, worsens AKI outcomes, and is a novel therapeutic target for AKI.

Protective Effect of Alkaline Mineral Water on Calcium Oxalate-Induced Kidney Injury in Mice.

Kidney stone disease induces chronic renal insufficiency by crystal-induced renal tubular epithelial cell injury. It has been reported that the prevalence of kidney stone disease is increasing, accompanied by the high recurrence rate. Alkaline mineral water has been reported to possess beneficial effects to attenuate inflammation. Here, we explored the potential protective effects and underlying mechanisms of alkaline mineral water against calcium oxalate-induced kidney injury. We performed the mice kidney stone model by administering glyoxylate at 100 mg/kg once daily for 7 days. To assess the effects of alkaline mineral water on oxalate-induced kidney injury, mice drank different water (distilled water, natural mineral water at pH = 8.0, as well as natural mineral water at pH = 9.3) for 7 days, respectively, followed by glyoxylate exposure. After collection, crystal formation, kidney injury and cell apoptosis, fibrosis, oxidative stress, as well as inflammation were measured. Our results showed that glyoxylate treatment led to kidney crystal formation and fibrosis, which can be attenuated by drinking alkaline mineral water. Furthermore, alkaline mineral water also reduced kidney injury and cell apoptosis, oxidative stress, and inflammation. Alkaline mineral water supplement prevents progression of glyoxylate-induced kidney stones through alleviating oxidative stress and inflammation.

Costunolide prevents renal ischemia-reperfusion injury in rats by reducing autophagy, apoptosis, inflammation, and DNA damage.

Renal ischemia-reperfusion (I/R) is a vital health condition leading to acute kidney injury. Costunolide (COST) is an actively used molecule clinically for its anti-inflammatory, antioxidant, and immunomodulatory properties. In the present study, we searched for the possible protective effects of COST against renal ischemia/reperfusion (I/R) injury in rats. We established a renal I/R rat model. We divided forty rats into four groups: group I (sham), group II (I/R), group III (I/R+COST 5 mg/kg), and group IV (I/R+COST 10 mg/kg). We collected blood, kidney, and lung samples for analysis. COST administration performed anti-oxidant and anti-inflammatory activity by reducing oxidant parameters and proinflammatory cytokine levels. COST alleviated DNA damage through declining 8-hydroxydeoxyguanosine (8-OHdG) levels. In addition, COST diminished tubular damage and inflammation by reducing kidney injury molecule-1 (KIM-1) production. COST administration also ameliorated apoptosis and autophagy by decreasing caspase-3 and microtubule-associated protein light chain 3B (MAPLC3, LC3B) expression. COST demonstrated protective effects against renal I/R-induced injury.

Malate reduced kidney injury molecule (KIM-1) expression and selectively upregulated the renal nitric oxide production in obstructive nephropathy

Malate, the tricarboxylic acid (TCA) cycle intermediary, upregulates renal nitric oxide (NO) signaling, and NO is renoprotective in nephropathy. This study explored the hypothesis that malate could increase renal NO and decrease renal injury and fibrotic markers in obstructive nephropathy. Kidney injury was induced in rats via unilateral surgical ligation of the ureter, there after, rats were treated with malate (600 mg/kg, p.o.) for ten days. Urine was collected on days 0, 4, 7 and 10. Urinary sodium excretion was also determined. Western blot and biochemical analyses were carried on the nephropathic kidneys. Malate reduced kidney injury molecule (KIM-1) expression in the renal cortex and medulla of nephropathic rats (p < 0.05). NO production was selectively increased in the medulla of nephropathic rats treated with malate (58.3 ± 1.3 vs 77.8 ± 4.4 µM/ng, p < 0.05). Superoxide dismutase and catalase activity increased in the kidney of malate-treated nephropathic rats (p < 0.05). Transforming growth factor (TGF-β), an index of fibrosis, increased in the cortex but not medulla of the malate-treated UUO group. There was a consistent increase in collagenase activity in the cortex, and a reduction in the medulla. Malate ameliorated the injury and inflammation but selectively reduced fibrosis in obstructive nephropathy (Fig. 6, Ref. 32). Text in PDF www.elis.sk Keywords: Malate, tricarboxylic acid cycle, nitric oxide, kidney injury molecule (KIM-1), obstructive nephropathy.

Contrast-induced acute kidney injury and its contemporary prevention.

The complexity and application range of interventional and diagnostic procedures using contrast media (CM) have recently increased. This allows more patients to undergo procedures that involve CM administration. However, the intrinsic CM toxicity leads to the risk of contrast-induced acute kidney injury (CI-AKI). At present, effective therapy of CI-AKI is rather limited. Effective prevention of CI-AKI therefore becomes crucially important. This review presents an in-depth discussion of CI-AKI incidence, pathogenesis, risk prediction, current preventive strategies, and novel treatment possibilities. The review also discusses the difference between CI-AKI incidence following intraarterial and intravenous CM administration. Factors contributing to the development of CI-AKI are considered in conjunction with the mechanism of acute kidney damage. The need for ultimate risk estimation and the prediction of CI-AKI is stressed. Possibilities of CI-AKI prevention is evaluated within the spectrum of existing preventive measures aimed at reducing kidney injury. In particular, the review discusses intravenous hydration regimes and pre-treatment with statins and N-acetylcysteine. The review further focuses on emerging alternative imaging technologies, alternative intravascular diagnostic and interventional procedures, and new methods for intravenous hydration guidance; it discusses the applicability of those techniques in complex procedures and their feasibility in current practise. We put emphasis on contemporary interventional cardiology imaging methods, with a brief discussion of CI-AKI in non-vascular and non-cardiologic imaging and interventional studies.

Roles of Mitochondrial DNA Damage in Kidney Diseases: A New Biomarker

The kidney is a mitochondria-rich organ, and kidney diseases are recognized as mitochondria-related pathologies. Intact mitochondrial DNA (mtDNA) maintains normal mitochondrial function. Mitochondrial dysfunction caused by mtDNA damage, including impaired mtDNA replication, mtDNA mutation, mtDNA leakage, and mtDNA methylation, is involved in the progression of kidney diseases. Herein, we review the roles of mtDNA damage in different setting of kidney diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD). In a variety of kidney diseases, mtDNA damage is closely associated with loss of kidney function. The level of mtDNA in peripheral serum and urine also reflects the status of kidney injury. Alleviating mtDNA damage can promote the recovery of mitochondrial function by exogenous drug treatment and thus reduce kidney injury. In short, we conclude that mtDNA damage may serve as a novel biomarker for assessing kidney injury in different causes of renal dysfunction, which provides a new theoretical basis for mtDNA-targeted intervention as a therapeutic option for kidney diseases.

Neonatal hypoxic ischemic encephalopathy increases acute kidney injury urinary biomarkers in a rat model.

Hypoxic ischemic encephalopathy (HIE) is associated with acute kidney injury (AKI) in neonates with birth asphyxia. This study aimed to utilize urinary biomarkers to characterize AKI in an established neonatal rat model of HIE. Day 7 Sprague-Dawley rat pups underwent HIE using the Rice-Vannucci model (unilateral carotid ligation followed by 120 mins of 8% oxygen). Controls included no surgery and sham surgery. Weights and urine for biomarkers (NGAL, osteopontin, KIM-1, albumin) were collected the day prior, daily for 3 days post-intervention, and at sacrifice day 14. Kidneys and brains were processed for histology. HIE pups displayed histological evidence of kidney injury including damage to the proximal tubules, consistent with resolving acute tubular necrosis, and had significantly elevated urinary levels of NGAL and albumin compared to sham or controls 1-day post-insult that elevated for 3 days. KIM-1 significantly increased for 2 days post-HIE. HIE did not significantly alter osteopontin levels. Seven days post-start of experiment, controls were 81.2% above starting weight compared to 52.1% in HIE pups. NGAL and albumin levels inversely correlated with body weight following HIE injury. The AKI produced by the Rice-Vannucci HIE model is detectable by urinary biomarkers, which can be used for future studies of treatments to reduce kidney injury.

Beneficial effects of bempedoic acid treatment in polycystic kidney disease cells and mice.

ADPKD has few therapeutic options. Tolvaptan slows disease but has side effects limiting its tolerability. Bempedoic acid (BA), an ATP citrate-lyase (ACLY) inhibitor FDA-approved for hypercholesterolemia, catalyzes a key step in fatty acid/sterol synthesis important for cell proliferation. BA is activated by very long-chain acyl-CoA synthetase (FATP2) expressed primarily in kidney and liver. BA also activates AMPK. We hypothesized that BA could be a novel ADPKD therapy by inhibiting cyst growth, proliferation, injury, and metabolic dysregulation via ACLY inhibition and AMPK activation. Pkd1-null kidney cell lines derived from mouse proximal tubule (PT) and collecting duct (IMCD) were grown in 2D or 3D Matrigel cultures and treated ± BA, ± SB-204990 (another ACLY inhibitor) or with Acly shRNA before cyst analysis, immunoblotting or mitochondrial assays using MitoSox and MitoTracker staining. Pkd1 fl/fl ; Pax8-rtTA; Tet-O-Cre C57BL/6J mice were induced with doxycycline injection on postnatal days 10 and 11 (P10-P11) and then treated ± BA (30mg/kg/d) ± tolvaptan (30-100mg/kg/d) by gavage from P12-21. Disease severity was determined by % total-kidney-weight-to-bodyweight (%TKW/BW) and BUN levels at euthanasia (P22). Kidney and liver homogenates were immunoblotted for expression of key biomarkers. ACLY expression and activity were upregulated in Pkd1-null PT and IMCD-derived cells vs. controls. Relative to controls, both BA and SB-204990 inhibited cystic growth in Pkd1-null kidney cells, as did Acly knockdown. BA inhibited mitochondrial superoxide production and promoted mitochondrial elongation, suggesting improved mitochondrial function. In ADPKD mice, BA reduced %TKW/BW and BUN to a similar extent as tolvaptan vs. untreated controls. Addition of BA to tolvaptan caused a further reduction in %TKW/BW and BUN vs. tolvaptan alone. BA generally reduced ACLY and stimulated AMPK activity in kidneys and livers vs. controls. BA also inhibited mTOR and ERK signaling and reduced kidney injury markers. In liver, BA treatment, both alone and together with tolvaptan, increased mitochondrial biogenesis while inhibiting apoptosis. We conclude that BA and ACLY inhibition inhibited cyst growth in vitro, and BA decreased ADPKD severity in vivo. Combining BA with tolvaptan further improved various ADPKD disease parameters. Repurposing BA may be a promising new ADPKD therapy, having beneficial effects alone and along with tolvaptan.

Intermittent hilar occlusion attenuates or prevents renal ischaemia-reperfusion in mice

BackgroundA minimal decrease in renal function in partial nephrectomy is an important clinical and experimental research objective. We compared the effect of intermittent hilar occlusion (IHO) and continuous hilar occlusion (CHO) on kidney injury and oxidative damage. MethodUsing CHO or IHO for 24, 30, and 45 min, intraoperative ischaemia, as well as a sham group, were set up in an ischaemia-reperfusion long-term survival mouse model. Renal function, pathological injury, subcellular structure injury, and cell apoptosis were evaluated at 1, 30, and 90 d postoperatively to study the protective effect of IHO. To do so, oxidative damage analysis, antioxidant activities, and ischaemia time dose-response curves on relative acute renal function injury were analysed. ResultsAll parameters indicated that kidney injury was dramatically attenuated in the IHO groups compared to those in the corresponding CHO groups. Particularly, mice in the IHO 24-min group incurred no tubular injury or renal functional injury; mice in the CHO 30-min group incurred severe acute and chronic kidney injury, but mice in the IHO 30-min group only experienced transient mild renal functional injury. IHO prolonged tolerable ischaemia duration. ConclusionsIHO can prolong the duration of tolerable ischaemia, at least partly through protecting the kidney from oxidative stress, consequently attenuating or preventing renal ischaemia-reperfusion injury. Reduced kidney injury after ischaemia-reperfusion is linked to a greater maintenance of antioxidant activity and less oxidative damage. The protective effect of IHO can be extremely efficient if properly applied; IHO may avoid renal ischaemia-reperfusion injury during partial nephrectomy.

Comparison of retrograde intrarenal stone surgery with and without a ureteral access sheath using kidney injury molecule-1 (KIM-1) levels: a prospective randomized study.

The objective is to compare patients who underwent retrograde intrarenal surgery with and without a ureteral access sheath (UAS) using kidney injury molecule-1 (KIM-1) levels. We also examined the difference in kidney damage between standard and dual lumen UAS. Sixty patients diagnosed with kidney stones and scheduled for RIRS were randomized into three groups: RIRS without UAS (Group 1), 11Fr/13Fr Boston scientific Navigator™ UAS (Group 2), and 11Fr/13Fr dual lumen ClearPetra™ UAS (Group 3). Data were prospectively collected in consecutive patients. Urine KIM-1/Cr levels were measured preoperatively, at postoperative 4 h, and on a postoperative day 14. Stone size, location, number, pre- and postoperative stent use, operation time, stone-free rate (SFR), post-ureteroscopic lesion scale (PULS) grade, hospitalization duration, and complications were recorded. There was no significant difference in demographical parameters and preoperative KIM-1/Cr levels among the groups. Postoperative 4th-hour urine KIM-1/Cr levels were higher in patients without UAS than patients with UAS (1.86, 0.67, 0.63 Groups 1, 2, 3, respectively). In comparing group 1 with groups 2 and 3 separately, Group 1 had a statistically significantly higher value than both groups (p = 0.002, p = 0.001, respectively). According to UAS type, there was no significant difference between groups 2 and 3. The use of UAS during RIRS has been shown to reduce kidney injury in the evaluation with KIM-1. Different UAS types on kidney injury and which one can protect the kidneys more during the procedure; will be elucidated by prospective randomized studies involving larger patient groups and UAS types.

Juniperus communis extract ameliorates lipopolysaccharide-induced acute kidney injury through the adenosine monophosphate-activated protein kinase pathway.

Septic shock can aggravate organ dysfunction and even lead to death. Juniperus communis (JCo) extract has been experimentally demonstrated to have anti‐inflammatory and antioxidant effects. We investigated the anti‐inflammatory and antioxidant mechanism of JCo extract in vivo and in vitro. In a lipopolysaccharide (LPS)‐induced acute kidney injury rat model, JCo extract improved animal survival, reduced kidney injury scores, suppressed kidney injury molecule‐1, and preserved E‐cadherin expression from LPS damage, as demonstrated by the immunohistochemistry examinations of the rat kidneys. In LPS‐stimulated NRK‐52E cells, JCo extract inhibited nuclear factor‐κB (NF‐κB) and increased adenosine monophosphate–activated protein kinase (AMPK) expression, prompting the activation of the antioxidant nuclear factor erythroid 2–related factor‐2/heme oxygenase‐1 pathway against oxidative stress. JCo extract ameliorated LPS‐induced acute kidney injury by suppressing NF‐κB signaling and stimulating the release of tumor necrosis factor‐α and interleukin‐1β through the AMPK pathway.