Against Acute Kidney Injury Research Articles

Macrophage autophagy protects against acute kidney injury by inhibiting renal inflammation through the degradation of TARM1

ABSTRACT Macroautophagy/autophagy activation in renal tubular epithelial cells protects against acute kidney injury (AKI). However, the role of immune cell autophagy, such as that involving macrophages, in AKI remains unclear. In this study, we discovered that macrophage autophagy was an adaptive response during AKI as mice with macrophage-specific autophagy deficiency (atg5 −/−) exhibited higher serum creatinine, more severe renal tubule injury, increased infiltration of ADGRE1/F4/80+ macrophages, and elevated expression of inflammatory factors compared to WT mice during AKI induced by either LPS or unilateral ischemia-reperfusion. This was further supported by adoptive transfer of atg5 −/− macrophages, but not WT macrophages, to cause more severe AKI in clodronate liposomes-induced macrophage depletion mice. Similar results were also obtained in vitro that bone marrow-derived macrophages (BMDMs) lacking Atg5 largely increased pro-inflammatory cytokine expression in response to LPS and IFNG. Mechanistically, we uncovered that atg5 deletion significantly upregulated the protein expression of TARM1 (T cell-interacting, activating receptor on myeloid cells 1), whereas inhibition of TARM1 suppressed LPS- and IFNG-induced inflammatory responses in atg5 −/− RAW 264.7 macrophages. The E3 ubiquitin ligases MARCHF1 and MARCHF8 ubiquitinated TARM1 and promoted its degradation in an autophagy-dependent manner, whereas silencing or mutation of the functional domains of MARCHF1 and MARCHF8 abolished TARM1 degradation. Furthermore, we found that ubiquitinated TARM1 was internalized from plasma membrane into endosomes, and then recruited by the ubiquitin-binding autophagy receptors TAX1BP1 and SQSTM1 into the autophagy-lysosome pathway for degradation. In conclusion, macrophage autophagy protects against AKI by inhibiting renal inflammation through the MARCHF1- and MARCHF8-mediated degradation of TARM1. Abbreviations: AKI, acute kidney injury; ATG, autophagy related; Baf, bafilomycin A1; BMDMs, bone marrow-derived macrophages; CCL2/MCP-1, C-C motif chemokine ligand 2; CHX, cycloheximide; CQ, chloroquine; IFNG, interferon gamma; IL, interleukin; IR, ischemia-reperfusion; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; LPS, lipopolysaccharide; MARCHF, membrane associated ring-CH-type finger; NC, negative control; NFKB, nuclear factor of kappa light polypeptide gene enhancer in B cells; NLRP3, NLR family, pyrin domain containing 3; NOS2, nitric oxide synthase 2, inducible; Rap, rapamycin; Wort, wortmannin; RT-qPCR, real-time quantitative polymerase chain reaction; Scr, serum creatinine; SEM, standard error of mean; siRNA, small interfering RNA; SYK, spleen tyrosine kinase; TARM1, T cell-interacting, activating receptor on myeloid cells 1; TAX1BP1, Tax1 (human T cell leukemia virus type I) binding protein 1; TECs, tubule epithelial cells; TNF, tumor necrosis factor; WT, wild type.

SGLT2 inhibition promotes glomerular repopulation by cells of renin lineage in experimental kidney disease.

Sodium glucose co-transporter-2 (SGLT2) inhibitors stimulate renal excretion of sodium and glucose and exert renal protective effects in patients with (non-)diabetic chronic kidney disease (CKD) and may as well protect against acute kidney injury (AKI). The mechanism behind this kidney protective effect remains unclear. Juxtaglomerular cells of renin lineage (CoRL) have been demonstrated to function as progenitors for multiple adult glomerular cell types in kidney disease. This study assesses the impact of SGLT2 inhibition on the repopulation of glomerular cells by CoRL and examines their phenotypic commitment. Experiments were performed in Ren1cre-tdTomato lineage-trace mice. Either 5/6 nephrectomy (5/6NX) modeling CKD or bilateral ischaemia reperfusion injury (bIRI) mimicking AKI was applied, while the SGLT2 inhibitor empagliflozin (10 mg/kg) was administered daily via oral gavage for 14 days. Both 5/6NX and bIRI-induced kidney injury increased the number of glomerular CoRL-derived cells. SGLT2 inhibition improved kidney function after 5/6NX, indicated by decreased blood creatinine and urea levels, but not after bIRI. In line with this, empagliflozin in 5/6NX animals resulted in less glomerulosclerosis, while it did not affect histopathological features in bIRI. Treatment with empagliflozin resulted in an increase in the number of CoRL-derived glomerular cells in both 5/6NX and bIRI conditions. Interestingly, SGLT2 inhibition led to more CoRL-derived podocytes in 5/6NX animals, whereas empagliflozin-treated bIRI mice presented with increased levels of parietal epithelial and mesangial cells derived from CoRL. We conclude that SGLT2 inhibition by empagliflozin promotes CoRL-mediated glomerular repopulation with selective CoRL-derived cell types depending on the type of experimental kidney injury. These findings suggest a previously unidentified mechanism that could contribute to the renoprotective effect of SGLT2 inhibitors.

Mirabegron, dependent on β3-adrenergic receptor, alleviates mercuric chloride-induced kidney injury by reversing the impact on the inflammatory network, M1/M2 macrophages, and claudin-2

The β3-adrenergic receptor (β3-AR) agonism mirabegron is used to treat overactive urinary bladder syndrome; however, its role against acute kidney injury (AKI) is not unveiled, hence, we aim to repurpose mirabegron in the treatment of mercuric chloride (HgCl2)-induced AKI. Rats were allocated into normal, normal + mirabegron, HgCl2 untreated, HgCl2 + mirabegron, and HgCl2 + the β3-AR blocker SR59230A + mirabegron. The latter increased the mRNA of β3-AR and miR-127 besides downregulating NF-κB p65 protein expression and the contents of its downstream targets iNOS, IL-4, -13, and -17 but increased that of IL-10 to attest its anti-inflammatory capacity. Besides, mirabegron downregulated the protein expression of STAT-6, PI3K, and ERK1/2, the downstream targets of the above cytokines. Additionally, it enhanced the transcription factor PPAR-α but turned off the harmful hub HNF-4α/HNF-1α and the lipid peroxide marker MDA. Mirabegron also downregulated the CD-163 protein expression, which besides the inhibited correlated cytokines of M1 (NF-κB p65, iNOS, IL-17) and M2 (IL-4, IL-13, CD163, STAT6, ERK1/2), inactivated the macrophage phenotypes. The crosstalk between these parameters was echoed in the maintenance of claudin-2, kidney function-related early (cystatin-C, KIM-1, NGAL), and late (creatinine, BUN) injury markers, besides recovering the microscopic structures. Nonetheless, the pre-administration of SR59230A has nullified the beneficial effects of mirabegron on the aforementioned parameters. Here we verified that mirabegron can berepurposedto treat HgCl2-induced AKI by activating the β3-AR. Mirabegron signified its effect by inhibiting inflammation, oxidative stress, and the activated M1/M2 macrophages, events that preserved the proximal tubular tight junction claudin-2 via the intersection of several trajectories.

Phytocompounds from Amazonian Plant Species against Acute Kidney Injury: Potential Nephroprotective Effects.

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.

TJ-17 (Goreisan) mitigates renal fibrosis in a mouse model of folic acid-induced chronic kidney disease

Background and purposeTJ-17 (Goreisan), a traditional Japanese Kampo medicine, has been generally used to treat edema, such as heart failure, due to its diuretic effect. In the present study, we investigate the effects of TJ-17 on chronic kidney disease (CKD). MethodsWe the preventive action of TJ-17 against acute kidney injury (AKI) transition to CKD in vivo using a folic acid (FA)-induced mouse model. Mice were treated with food containing TJ-17 at 48 h after FA intraperitoneal injection (AKI phase). ResultsHistological analysis, as well as renal function and renal injury markers, deteriorated in mice with FA-induced CKD and were ameliorated by TJ-17 treatment. Increased levels of inflammatory cytokines and macrophage infiltration were also alleviated in mice treated with TJ-17. Renal fibrosis, a crucial factor in CKD, was induced by FA administration and inhibited by TJ-17 treatment. Pretreatment with TJ-17 did not exert an inhibitory effect on FA-induced AKI. The increase in urinary volume in FA-induced CKD mice was ameliorated by TJ-17 treatment, with a concurrent correction of reduced aquaporins expression in the kidney. ConclusionTJ-17 may have a novel preventive effect against inflammation, oxidative stress, and fibrosis, contributing to innovation in the treatment of CKD.

Pregnane X receptor activation alleviates renal fibrosis in mice via interacting with p53 and inhibiting the Wnt7a/β-catenin signaling.

Renal fibrosis is a common pathological feature of chronic kidney disease (CKD) with various etiologies, which seriously affects the structure and function of the kidney. Pregnane X receptor (PXR) is a member of the nuclear receptor superfamily and plays a critical role in regulating the genes related to xenobiotic and endobiotic metabolism in mammals. Previous studies show that PXR is expressed in the kidney and has protective effect against acute kidney injury (AKI). In this study, we investigated the role of PXR in CKD. Adenine diet-induced CKD (AD) model was established in wild-type and PXR humanized (hPXR) mice, respectively, which were treated with pregnenolone-16α-carbonitrile (PCN, 50 mg/kg, twice a week for 4 weeks) or rifampicin (RIF, 10 mg·kg-1·d-1, for 4 weeks). We showed that both PCN and RIF, which activated mouse and human PXR, respectively, improved renal function and attenuated renal fibrosis in the two types of AD mice. In addition, PCN treatment also alleviated renal fibrosis in unilateral ureter obstruction (UUO) mice. On the contrary, PXR gene deficiency exacerbated renal dysfunction and fibrosis in both adenine- and UUO-induced CKD mice. We found that PCN treatment suppressed the expression of the profibrotic Wnt7a and β-catenin in AD mice and in cultured mouse renal tubular epithelial cells treated with TGFβ1 in vitro. We demonstrated that PXR was colocalized and interacted with p53 in the nuclei of tubular epithelial cells. Overexpression of p53 increased the expression of Wnt7a, β-catenin and its downstream gene fibronectin. We further revealed that p53 bound to the promoter of Wnt7a gene to increase its transcription and β-catenin activation, leading to increased expression of the downstream profibrotic genes, which was inhibited by PXR. Taken together, PXR activation alleviates renal fibrosis in mice via interacting with p53 and inhibiting the Wnt7a/β-catenin signalingpathway.

The Impact of Preprocedural Statin Use on Acute Kidney Injury and Mortality in Patients Undergoing Peripheral Vascular Intervention

Current evidence suggests that statins may be protective against acute kidney injury (AKI) following angiography. We sought to assess the effect of statin use on outcomes following peripheral vascular intervention (PVI). We identified all patients undergoing PVI in the Vascular Quality Initiative (VQI) from 2003 to 2020 and excluded patients with history of dialysis or prior renal transplant. We compared postintervention outcomes in patients who were on preoperative statin medications to those who were not on a statin prior to PVI. Outcomes of interest were in-hospital AKI, myocardial infarction (MI), and in-hospital and 30-day mortality, assessed by multivariable logistic regression. Outcomes were also stratified by pre-existing chronic kidney disease (glomerular filtration rate [GFR] <60 and ≥60 mL/min/1.73m2). Among 110,266 patients, 81,807 (74%) were on preoperative statins and 28,459 (26%) were not. Patients receiving statins had lower rates of post-procedure AKI compared with those not taking statins (0.93% vs 1.1%; odds ratio [OR], 0.85; 95% confidence interval [CI], 0.74-0.97), as well as lower rates of in-hospital mortality (0.56% vs 1.0%; OR, 0.54; 95% CI, 0.47-0.63) and 30-day mortality (1.3% vs 2.4%; OR, 0.55; 95% CI, 0.49-0.61). After adjustment, statin use was associated with lower odds of AKI (adjusted OR [aOR], 0.79; 95% CI, 0.63-0.99), in-hospital MI (aOR, 0.65; 95% CI, 0.44-0.97), in-hospital mortality (aOR, 0.58; 95% CI, 0.43-0.78), and 30-day mortality (aOR, 0.68; 95% CI, 0.54-0.86). After stratifying by preoperative renal function, there was no association between statin usage and AKI in patients with normal GFR ≥60 mL/min/1.73m2 (aOR, 1.14; 95% CI, 0.20-6.31). However, in patients with GFR <60 mL/min/1.73m2, statin use was associated with 22% lower odds of developing AKI after PVI (aOR, 0.78; 95% CI, 0.62-0.98), as well as lower odds of in-hospital MI (aOR, 0.63; 95% CI, 0.42-0.95), in-hospital mortality (aOR, 0.56; 95% CI, 0.42-0.76), and 30-day mortality (aOR, 0.69; 95% CI, 0.54-0.87) (Table I). Pre-procedural statin use is associated with lower incidence of AKI following PVI, as well as lower in-hospital MI, in-hospital mortality, and 30-day mortality rates, particularly in patients with pre-existing renal dysfunction. Statins should be considered for renal protection prior to PVI, in addition to the current strategies of pre-hydration and minimization of contrast usage. Despite current guidelines and evidence of clinical benefits, statins continue to be significantly underused in the vascular population. Additional work is needed to improve the adoption of statins in patients with peripheral vascular disease.TableAdjusted odds ratios (aORs) for outcomes following peripheral vascular intervention (PVI) in patients on statins vs patients not on statins as reference groupEndpointPrimary cohort (N = 110,266)GFR ≥60 mL/min/1.73m2 (n = 70,752)GFR <60 mL/min/1.73m2 (n = 39,514)aOR [95% CI]P-valueaOR [95% CI]P-valueaOR [95% CI]P-valueIn-hospitalAKI0.79 [0.63-0.99].0450.14 [0.20-6.31].8830.78 [0.61-0.98].037In-hospitalMI0.65 [0.44-0.98].0380.81 [0.04-18.57].8960.63 [0.42-0.95].028In-hospital mortality0.58 [0.43-0.78]<.001a–0.56 [0.42-0.76]<.00130-day mortality0.68 [0.54-0.86].0010.04 [0.02-0.72]a.0290.69 [1.92-1.23].001AKI, Acute kidney injury; CI, confidence interval; GFR, glomular filtration rate; MI, myocardial infarction.All models adjusted for age, sex, race/ethnicity, smoking status, chrnic obstructive pulmonary disease, hypertension, diabetes, coronary artery disease, congestive heart failure, preoperative medications (aspirin, P2Y12 inhibitor, anticoagulation), procedure urgency, disease severity, contrast volume used, use of CO2 contrast, and use of contrast-induced nephritis prophylaxis; GFR was also included in the primary model.Boldface P-values indicate statistical significance.aAll in-hospital deaths occurred in patients not on statins in the normal GFR subgroup. Open table in a new tab

Ischemic postconditioning protects against acute kidney injury after limb ischemia reperfusion by regulating HMGB1 release and autophagy

Ischemic postconditioning (I-PostC) has a protective effect against acute kidney injury (AKI) induced by limb ischemia–reperfusion (LIR); however, the exact mechanism remains to be elucidated. Our study aims to investigate the potential involvement of high-mobility group box 1 protein (HMGB1) and autophagy in renoprotection generated by I-PostC. A rat model of LIR-induced AKI was established and rats were randomly assigned to five groups: (i) sham-operated control, (ii) I/R, (iii) I/R + I-PostC, (iv) I/R + I-PostC + rapamycin (autophagy activator), and (v) I/R + I-PostC + 3-methyladenine (autophagy inhibitor). Morphological changes in the kidneys were assessed by histology, and ultrastructural changes in renal tubular epithelial cells and glomerular podocytes were observed by transmission electron microscopy. The levels of kidney function parameters, serum inflammatory factors, and autophagy markers were detected. The results showed that the levels of HMGB1, Beclin1, LC3-II/LC3-I, and inflammatory cytokines (TNF-α and IL-6) were significantly higher in the I/R group compared to the sham control in serum and in renal tissues. I-PostC significantly reduced the levels of HMGB1, Beclin1, LC3-II/LC3-I, and inflammatory cytokines in renal tissues and improved renal function. Renal histopathology and ultrastructural observations indicated that I-PostC alleviated renal tissue injury. In addition, rapamycin (autophagy activator) treatment increased the levels of inflammatory cytokine expression levels and decreased renal function, reversed the protective effect of I-PostC against LIR-induced AKI. In conclusion, I-PostC could play a protective role against AKI by regulating the release of HMGB1 and inhibiting autophagy activation.

Oral hydrogel microspheres were used for highly specific delivery of Steamed Codonopsis lanceolata to exert the protective effects on cisplatin-induced acute kidney injury in mice

Although Steamed Codonopsis lanceolata (SCL) has been shown to protect against acute kidney injury (AKI), Its poor stability and susceptibility to decomposition in the GI tract significantly reducing its therapeutic efficacy. Nanoscale/microscale drug delivery systems may overcome the difficulties of oral administration of phytochemicals and avoid premature drug release and degradation. In this study, we mainly loaded SCL into sodium alginate (SA) micron particles (SCL-SA), which showed significant gut-targeting and anti-gastric acid ability from in vitro and in vivo imaging fluorescence adhesion experiments. Our results showed that the levels of serum blood urea nitrogen (BUN) and creatinine (CRE) were evidently increased in cisplatin-intoxicated mice, which were reversed by SCL-SA. Renal oxidative stress, evidenced by increasing malondialdehyde (MDA) level and decrease of glutathione (GSH), catalase (CAT) and superoxide dismutase (SOD) activities, were significantly alleviated by SCL-SA pretreatment. Immunohistochemical staining showed that SCL-SA could improve cell apoptosis by decrease the expressions of BCL2-Associated X (Bax) and B-cell lymphoma-2 (Bcl-2). In addition, SCL-SA pretreatment can also inhibit the increase of serum tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) induced by cisplatin. Additionally, SCL-SA was found to reduce the expressions of nuclear factor-κB (NF-κB) signal pathways and inflammatory protein levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) induced by cisplatin. Meanwhile, the contents of lobetyolin and syringin in Codonopsis lanceolata were increased after steaming. In conclusion, the reduction of AKI by SCL-SA may be due to the synergistic effect of lobetyolin and syringin. Based on the advantages of microparticles, this study provides important insights into the treatment of AKI with oral natural compounds.

Gamma oryzanol loaded into micelle-core/chitosan-shell: from translational nephroprotective potential to emphasis on sirtuin-1 associated machineries

Gamma oryzanol (ORZ) is a nutraceutical that is poorly water soluble with poor intestinal absorption. In the current work, ORZ was nanoformulated into uncoated and chitosan coated micelles based on methoxy-poly(ethylene glycol)-b-poly(ε-caprolactone) (mPEG-PCL) and poly(ε-caprolactone)-b-methoxy-poly(ethylene glycol)-b-poly(ε-caprolactone) (PCL-PEG-PCL) copolymers for augmenting ORZ oral delivery. The physicochemical properties, morphological study, in-vitro release and safety of the nanoplaforms were determined. Importantly, the nephroprotective competence of the nanoplaforms was analyzed against acute kidney injury (AKI) rat model and the sirtuin-1 associated machineries were assessed. The results revealed that the micelles exerted particle size (PS) from 97.9 to 117.8 nm that was markedly increased after chitosan coating. The reversal of zeta potential from negative to highly positive further confirmed efficient coating. In vitro release profiles demonstrated prolonged release pattern. The nanoforms conferred higher cell viability values than free ORZ on Vero cell line. The designed micelles displayed augmented nephroprotection compared to free ORZ with the supremacy of CS coated micelles over uncoated ones in restoring kidney parameters to normal levels. The attenuated AKI was fulfilled via the modulation of sirtuin-1 signaling pathways translated by restoring the histological features, increasing renal antioxidant states, renal autophagy and decreasing renal inflammation and renal apoptosis. These outcomes confirmed that surface modification with chitosan had a considerable leverage on micelles safety, release behavior and in vivo performance.

Repeated Episodes of Ischemia/Reperfusion Induce Heme-Oxygenase-1 (HO-1) and Anti-Inflammatory Responses and Protects against Chronic Kidney Disease

Preconditioning episodes of ischemia/reperfusion (IR) induce protection against acute kidney injury (AKI), however their long-term effect still unknown. We evaluated AKI to chronic kidney disease (CKD) transition, after three-mild or three-severe episodes of IR. AKI was induced by single bilateral IR (1IR), or three episodes of IR separated by 10-day intervals (3IR) of mild (20 min) or severe (45 min) ischemia. Sham-operated rats served as controls. During 9-months, the 1IR group (20 or 45 min) developed CKD evidenced by progressive proteinuria and renal fibrosis. In contrast, the long-term adverse effects of AKI were markedly ameliorated in the 3IR group. The acute response in 3IR, contrasted with the 1IR group, that was characterized by an increment in heme oxygenase-1 (HO-1) and an anti-inflammatory response mediated by a NFkB-p65 phosphorylation and IL-6 decrease, together with an increase in TGF-β, and IL-10 expression, as well as in M2-macrophages. In addition, three episodes of IR downregulated endoplasmic reticulum (ER) stress markers expression, CHOP and BiP. Thus, repeated episodes of IR with 10-day intervals induced long-term renal protection accompanied with HO-1 overexpression and M2-macrophages increase.

Revisiting diuretic choice in chronic kidney disease.

Existing guidelines offer little direction about the use of thiazide and loop diuretics in patients with chronic kidney disease (CKD). This review summarizes recent studies impacting indications and safety considerations for these agents in patients with CKD. Chlorthalidone reduces blood pressure compared to placebo in patients with advanced CKD, challenging the belief that thiazide diuretics lose efficacy at lower glomerular filtration rates (GFR). Existing studies show no clear impact of thiazide or loop diuretic use on kidney or cardiovascular outcomes in patients with CKD. Sodium-glucose co-transporter type 2 (SGLT2) inhibitors have diuretic effects, but concomitant use of a diuretic does not diminish the preventive benefits of these agents against acute kidney injury (AKI). Despite theoretical concerns, thiazide diuretics likely do not worsen circulating vasopressin levels or cyst progression in polycystic kidney disease and may be useful for alleviating polyuria from tolvaptan. Diuretics cause multiple adverse effects, including electrolyte abnormalities, hemodynamic-mediated decrease in estimated GFR, and AKI. Recent evidence supports expanded indications for diuretics in patients with kidney disease, including chlorthalidone for hypertension in advanced CKD. Monitoring electrolytes and estimated GFR is critical to ensure patient safety when prescribing these agents for patients with CKD.

Selective EZH2 inhibitor zld1039 alleviates inflammation in cisplatin-induced acute kidney injury partially by enhancing RKIP and suppressing NF-κB p65 pathway.

Enhancer of zeste homolog 2 (EZH2), a component of polycomb repressive complex 2 (PRC2), is a histone lysine methyltransferase mediating trimethylation of histone H3 at lysine 27 (H3K27me3), which is a repressive marker at the transcriptional level. EZH2 sustains normal renal function and its overexpression has bad properties. Inhibition of EZH2 overexpression exerts protective effect against acute kidney injury (AKI). A small-molecule compound zld1039 has been developed as an efficient and selective EZH2 inhibitor. In this study, we evaluated the efficacy of zld1039 in the treatment of cisplatin-induced AKI in mice. Before injection of cisplatin (20 mg/kg, i.p.), mice were administered zld1039 (100, 200 mg/kg, i.g.) once, then in the following 3 days. We found that cisplatin-treated mice displayed serious AKI symptoms, evidenced by kidney dysfunction and kidney histological injury, accompanied by EZH2 upregulation in the nucleus of renal tubular epithelial cells. Administration of zld1039 dose-dependently alleviated renal dysfunction as well as the histological injury, inflammation and cell apoptosis in cisplatin-treated mice. We revealed that zld1039 administration exerted an anti-inflammatory effect in kidney of cisplatin-treated mice via H3K27me3 inhibition, raf kinase inhibitor protein (RKIP) upregulation and NF-κB p65 repression. In the cisplatin-treated mouse renal tubular epithelial (TCMK-1) cells, silencing of RKIP with siRNA did not abolish the anti-inflammatory effect of EZH2 inhibition, suggesting that RKIP was partially involved in the anti-inflammatory effect of zld1039. Collectively, EZH2 inhibition alleviates inflammation in cisplatin-induced mouse AKI via upregulating RKIP and blocking NF-κB p65 signaling in cisplatin-induced AKI. The potent and selective EZH2 inhibitor zld1039 has the potential as a promising agent for the treatment of AKI.

The protective mechanism of Klotho gene-modified bone marrow mesenchymal stem cells on acute kidney injury induced by rhabdomyolysis.

BackgroundStudies have shown that the Klotho gene has tremendous potential for future therapeutic purposes in both acute and chronic kidney diseases (CKD). This study aimed to investigate the possible protective mechanisms of the Klotho gene against acute kidney injury (AKI) induced by rhabdomyolysis (RM).MethodsIn this study, bone marrow mesenchymal stem cells (BMSCs) were transfected with recombinant adenoviruses expressing the Klotho gene (BMSCs-Klotho) and by those expressing empty vector (BMSCs-EV). After successful transfection, we tested the proliferation, secretion and migration abilities of the BMSCs-Klotho compared with those of the BMSCs-EV and BMSCs. Then, 30 male C57BL/6 mice were examined, with 6 mice randomly assigned to the control group (PBS injected into the tail vein, CON) or one of the four treatment groups treated with either BMSCs-Klotho (AKI+BMSCs-Klotho), BMSCs-EV (AKI+BMSCs-EV), BMSCs (AKI+BMSCs) or PBS (AKI+PBS) after induction of RM. Seventy-two h after treatment, serum creatinine (SCr) and blood urea nitrogen (BUN) levels were obtained to assess renal function, and renal tissue was obtained to measure kidney tissue damage. Additionally, kidney protective mechanism-related indexes, such as EPO, IGF-1, KIM-1 and HIF-1, were analysed using Western blot analysis and immunohistochemistry.ResultsThe results obtained showed that the proliferation, secretory and migration abilities of the BMSCs were significantly increased after transfection with the Klotho gene. Treatment with BMSCs-Klotho, BMSCs-EV or BMSCs improved renal function compared to treatment with PBS. However, the improvement observed in renal function in the BMSCs-Klotho group was better than that of the other groups. Histological analysis demonstrated that tissue damage was significantly decreased in the mice in the AKI+BMSCs-Klotho, AKI+BMSCs-EV or AKI+BMSCs groups compared to that in the mice in the AKI+PBS group. However, the best recovery was observed in the mice treated with BMSCs-Klotho concomitantly. Furthermore, the expression of protective factors erythropoietin (EPO) and insulin-like growth factor 1 (IGF-1) increased obviously, and the injury biomarkers kidney injury molecule 1 (KIM-1) and hypoxia inducible factor 1 (HIF-1) decreased notably in the group of BMSCs-Klotho, BMSCs-EV and BMSCs. Additionally, the levels of the aforementioned protein indicators in the AKI+BMSCs-Klotho group were not different from those in the CON group.ConclusionKlotho overexpression exerted positive effects on BMSCs and markedly promoted recovery from RM-induced AKI. These findings suggest that the overexpression of the Klotho gene might be a good candidate for further therapy for AKI in clinical trials.

Influence of age on gender-related differences in acute kidney injury after minimally invasive radical or partial nephrectomy.

Female gender is known to be protective against acute kidney injury (AKI) after radical or partial nephrectomy and estrogen is considered a protective factor. If estrogen is a major contributor to the protective effects of female gender against renal injury, these protective effects may be diminished in postmenopausal women. Therefore, this retrospective study investigated the influence of female age on gender-related differences in AKI after minimally invasive radical or partial nephrectomy. Patients who underwent minimally invasive radical (n = 765) or partial (n = 1161) nephrectomy were selected. These patients were stratified by gender and divided into three age categories considered to be pre, peri, and postmenopausal periods in women: ≤ 40years, 41-59years, and ≥ 60years, respectively. Adjusted logistic regression analyses were conducted to identify the risk of AKI according to gender and age. The incidence of AKI after radical or partial nephrectomy was significantly higher in men as compared to women in all age categories. Women aged ≥ 60years had a significantly increased risk of AKI as compared to women aged < 60years in radical nephrectomy, but not in partial nephrectomy. When compared with women aged ≥ 60years, men aged > 40years accompanied significantly higher risk of AKI following both radical and partial nephrectomy, even after adjusting confounders. However, men aged ≤ 40years had a similar risk of AKI after radical nephrectomy, but a significantly higher risk after partial nephrectomy as compared to women aged ≥ 60years. Male gender was associated with a higher risk of AKI after radical and partial nephrectomy as compared to postmenopausal women. This calls for more thorough preoperative counseling and renal protective strategies in male patients when undergoing radical and partial nephrectomy.

Honokiol Protects the Kidney from Renal Ischemia and Reperfusion Injury by Upregulating the Glutathione Biosynthetic Enzymes.

Glutathione (GSH) is an endogenous antioxidant found in plants, animals, fungi, and some microorganisms that protects cells by neutralizing hydrogen peroxide. Honokiol, an active ingredient of Magnolia officinalis, is known for antioxidant, anti-inflammatory, and anti-bacterial properties. We investigated the protective mechanism of honokiol through regulating cellular GSH in renal proximal tubules against acute kidney injury (AKI). First, we measured cellular GSH levels and correlated them with the expression of GSH biosynthetic enzymes after honokiol treatment in human kidney-2 (HK-2) cells. Second, we used pharmacological inhibitors or siRNA-mediated gene silencing approach to determine the signaling pathway induced by honokiol. Third, the protective effect of honokiol via de novo GSH biosynthesis was investigated in renal ischemia-reperfusion (IR) mice. Honokiol significantly increased cellular GSH levels by upregulating the subunits of glutamate-cysteine ligase (Gcl)—Gclc and Gclm. These increases were mediated by activation of nuclear factor erythroid 2-related factor 2, via PI3K/Akt and protein kinase C signaling. Consistently, honokiol treatment reduced the plasma creatinine, tubular cell death, neutrophil infiltration and lipid peroxidation in IR mice and the effect was correlated with upregulation of Gclc and Gclm. Conclusively, honokiol may benefit to patients with AKI by increasing antioxidant GSH via transcriptional activation of the biosynthetic enzymes.

Regenerative abilities of mesenchymal stem cells via acting as an ideal vehicle for subcellular component delivery in acute kidney injury.

Cell‐to‐cell communication and information exchange is one of the most important events in multiple physiological processes, including multicellular organism development, cellular function regulation, external stress response, homeostasis maintenance and tissue regeneration. New findings support the concept that subcellular component delivery may account for the beneficial effects of mesenchymal stem cell (MSC)‐based therapy‐mediated protection against acute kidney injury (AKI). Through the secretion of extracellular vesicles (EVs), formation of tunnelling nanotubes (TNTs) and development of cellular fusions, a broad range of subcellular components, including proteins, nucleic acids (mRNA and miRNA) or even organelles can be transferred from MSCs into injured renal cells, significantly promoting cell survival, favouring tissue repair and accelerating renal recovery. In this review, we outline an extensive and detailed description of the regenerative consequences of subcellular component delivery from MSCs into injured renal cells during AKI, by which the potential mechanism underlying MSC‐based therapies against AKI can be elucidated.

Lactobacillus salivarius BP121 prevents cisplatin‑induced acute kidney injury by inhibition of uremic toxins such as indoxyl sulfate and p‑cresol sulfate via alleviating dysbiosis

The gut microbiota is important for maintaining the integrity of the intestinal barrier, promoting immunological tolerance and carrying out metabolic activities that have not evolved in hosts. Intestinal dysbiosis is associated with chronic kidney disease and probiotic supplementation has been shown to be beneficial. However, it is not known whether gut microorganisms-specifically, lactic acid bacteria (LAB) can protect against acute kidney injury (AKI). To address this issue, the present study investigated the effects of Lactobacillus salivarius BP121, an intestinal LAB isolated from the feces of newborns, in a rat model of cisplatin-induced AKI and also in Caco-2 human intestinal epithelial cells. BP121 prevented cisplatin-induced AKI in rats, as demonstrated by decreases in inflammation and oxidative stress in kidney tissue and in serum levels of uremic toxins such as indoxyl sulfate (IS) and p-cresol sulfate (PCS). BP121 also reduced intestinal permeability, as determined using fluorescein isothiocyanate-dextran by immunohistochemical detection of tight junction (TJ) proteins such as zona occludens-1 and occludin. The abundance of Lactobacillus spp., which are beneficial intestinal flora, was increased by BP121; this was accompanied by an increase in the concentrations of short-chain fatty acids in feces. Additionally, H2O2-induced TJ protein damage was reduced in Caco-2 cells treated with BP121 culture supernatant, an effect that was reversed by the 5′ AMP-activated protein kinase (AMPK) inhibitor Compound C and Toll-like receptor (TLR)4 inhibitor TLR4-IN-C34. In conclusion, this study demonstrated that L. salivarius BP121 protects against cisplatin-induced AKI by decreasing inflammation and oxidative stress and this renoprotective effect is partially mediated by modulating the gut environment and thereby suppressing IS and PCS production as well as by regulating AMPK and TLR4 dependent TJ assembly.

Hexapeptide derived from prothymosin alpha attenuates cisplatin-induced acute kidney injury.

Prothymosin alpha (ProTα) is a nuclear protein expressed in virtually all mammalian tissues. Previous studies have shown that ProTα exhibits protective effects against ischemia-induced cell death in various cell types. Recently, the 6-residue peptide P6Q (NEVDQE), the modified form of the active 6-residue core (51-56) in ProTα, has also been shown to have protective effects against retinal ischemia. However, it remains to be elucidated whether P6Q is effective against acute kidney injury (AKI). Therefore, we investigated the renoprotective effect of P6Q on cisplatin-induced AKI. Cultured HK-2 cells were treated with cisplatin for 24h and pretreatment with ProTαor P6Qwas carried out 30 min before cisplatin treatment.Cell viability was evaluated using the MTT assay. In an in vivo study, 8-week-old male Wistar rats were divided into control, cisplatin treated, and cisplatin treated with P6Q injection groups. In the last of these, P6Q was injected intravenously before cisplatin treatment. Then, we evaluated the renoprotective effect of P6Q. In the study on cultured cells, pretreatment with ProTα or P6Q prevented cisplatin-induced cell death. In the in vivo study, pretreatment with P6Q significantly attenuated cisplatin-induced increase in serum creatinine and blood urea nitrogen levels, renal tubular cell injury, and apoptosis. Moreover, P6Q attenuated the mitochondrial apoptotic pathway and accelerated Akt phosphorylation after cisplatin-induced renal damage. Taken together, our findings indicate that P6Q can attenuate cisplatin-induced AKI and suppress the mitochondrial apoptotic pathway via Akt phosphorylation. These data suggest that P6Q has potential as a preventative drug for cisplatin-induced AKI.

Fluorofenidone protects against acute kidney injury.

Cisplatin (CP) is one of the most effective chemotherapeutics in the treatment of human cancers. However, the beneficial effects of CP are limited by the toxic effects, especially nephrotoxicity. Fluorofenidone (AKFPD) is a promising multifunctional antifibrosis pyridinone drug discovered by our group. But there is no evidence of its protective effects against acute kidney injury (AKI). Therefore, we investigated the protective effects of AKFPD on CP-induced AKI in vivo and in vitro. Compared with the model group, treatment with AKFPD effectively ameliorated kidney damages. In order to elucidate the mechanisms, we discovered that AKFPD treatment notably alleviated generation of reactive oxygen species, reduced the phosphorylation levels of MAPKs (ERK1 and 2, JNKs, and p38), suppressed inflammatory response, inhibited apoptosis, and abated the expression of CP transporters (organic cation transporter 2 and copper transport protein 1) compared with the model group. Moreover, because renal ischemia reperfusion injury (IRI)-induced AKI and LPS-induced AKI are the major models representative of renal transplantation-correlated AKI and sepsis-related AKI, which are also the main causes of AKI, we have also proved the effectiveness of AKFPD on these models. In conclusion, these findings suggest that AKFPD is a potent drug for CP-, IRI-, and LPS-caused AKI and elucidate the underlying mechanism.-Jiang, Y., Quan, J., Chen, Y., Liao, X., Dai, Q., Lu, R., Yu, Y., Hu, G., Li, Q., Meng, J., Xie, Y., Peng, Z., Tao, L. Fluorofenidone protects against acute kidney injury.