Repair Of Acute Kidney Injury Research Articles

Regulated necrosis role in inflammation and repair in acute kidney injury.

Acute kidney injury (AKI) frequently occurs in patients with chronic kidney disease (CKD) and in turn, may cause or accelerate CKD. Therapeutic options in AKI are limited and mostly relate to replacement of kidney function until the kidneys recover spontaneously. Furthermore, there is no treatment that prevents the AKI-to-CKD transition. Regulated necrosis has recently emerged as key player in kidney injury. Specifically, there is functional evidence for a role of necroptosis, ferroptosis or pyroptosis in AKI and the AKI-to-CKD progression. Regulated necrosis may be proinflammatory and immunogenic, triggering subsequent waves of regulated necrosis. In a paradigmatic murine nephrotoxic AKI model, a first wave of ferroptosis was followed by recruitment of inflammatory cytokines such as TWEAK that, in turn, triggered a secondary wave of necroptosis which led to persistent kidney injury and decreased kidney function. A correct understanding of the specific forms of regulated necrosis, their timing and intracellular molecular pathways may help design novel therapeutic strategies to prevent or treat AKI at different stages of the condition, thus improving patient survival and the AKI-to-CKD transition. We now review key regulated necrosis pathways and their role in AKI and the AKI-to-CKD transition both at the time of the initial insult and during the repair phase following AKI.

Exosomes Highlight Future Directions in the Treatment of Acute Kidney Injury

Acute kidney injury (AKI) is a severe health problem associated with high morbidity and mortality rates. It currently lacks specific therapeutic strategies. This review focuses on the mechanisms underlying the actions of exosomes derived from different cell sources, including red blood cells, macrophages, monocytes, mesenchymal stem cells, and renal tubular cells, in AKI. We also investigate the effects of various exosome contents (such as miRNA, lncRNA, circRNA, mRNA, and proteins) in promoting renal tubular cell regeneration and angiogenesis, regulating autophagy, suppressing inflammatory responses and oxidative stress, and preventing fibrosis to facilitate AKI repair. Moreover, we highlight the interactions between macrophages and renal tubular cells through exosomes, which contribute to the progression of AKI. Additionally, exosomes and their contents show promise as potential biomarkers for diagnosing AKI. The engineering of exosomes has improved their clinical potential by enhancing isolation and enrichment, target delivery to injured renal tissues, and incorporating small molecular modifications for clinical use. However, further research is needed to better understand the specific mechanisms underlying exosome actions, their delivery pathways to renal tubular cells, and the application of multi-omics research in studying AKI.

YAP nuclear translocation induced by HIF-1α prevents DNA damage under hypoxic conditions

Maladaptive repair of acute kidney injury (AKI) is associated with a high risk of developing chronic kidney disease deemed irremediable even in present days. When AKI arises from ischemia-reperfusion injury, hypoxia usually plays a major role. Although both hypoxia-inducible factor-1α (HIF-1α) and yes-associated protein (YAP) have been proven to promote renal cell survival under hypoxia, there is a lack of research that studies the crosstalk of the two and its effect on kidney repair. In studying the crosstalk, CoCl2 was used to create a mimetic hypoxic environment. Immunoprecipitation and proximity ligation assays were performed to verify protein interactions. The results show that HIF-1α interacts with YAP and promotes nuclear translocation of YAP at a high cell density under hypoxic conditions, suggesting HIF-1α serves as a direct carrier that enables YAP nuclear translocation. This is the first study to identify HIF-1α as a crucial pathway for YAP nuclear translocation under hypoxic conditions. Once translocated into a nucleus, YAP protects cells from DNA damage and apoptosis under hypoxic conditions. Since it is unlikely for YAP to translocate into a nucleus without HIF-1α, any treatment that fosters the crosstalk between the two holds the potential to improve cell recovery from hypoxic insults.

Induced pluripotent stem cells-podocytes promote repair in acute kidney injury is dependent on Mafb/CCR5/Nampt axis-mediated M2 macrophage polarization

Induced pluripotent stem cells (iPSCs) have been the focus of cellular therapy studies. The use of iPSCs in regenerative medicine is limited by their tumorigenic potential. This study sought to determine whether iPSCs-derived podocytes attenuate acute kidney injury (AKI) and the molecular mechanism. Inoculation of iPSCs-podocytes significantly promoted the repair of kidney injury in AKI mice, reduced the levels of kidney injury factors Scr, BUN, and urinary NAG, and alleviated the inflammatory response. Histological analysis revealed a significant increase in the number of M2 macrophages and a significant decrease in M1 macrophages in the kidney tissues. Subsequently, the genes and signaling pathways that may be associated with kidney injury repair in mice were analyzed by RNA-seq and bioinformatics prediction. The polarization of M2 macrophages was promoted by MAF bZIP transcription factor B (Mafb)-mediated activation of C-C motif chemokine receptor 5 (Ccr5) and nicotinamide phosphoribosyltransferase (Nampt) signaling pathway. Taken together, these results show that iPSCs-podocytes depend on Mafb to activate the Nampt signaling pathway through transcriptional activation of Ccr5, thereby promoting the repair of AKI caused by ischemia-reperfusion.

Review of the Benefits of Eggshell Content in Body Tissue Structure Repair

Eggshell (ES) is a waste material that cannot be consumed with low economic value. ES mainly contains calcium carbonate (CaCO3) and an organic matrix in the form of proteins, glycoproteins, and proteoglycans. Meanwhile, the eggshell membrane (ESM) contains osteopontin collagen, fibronectin, keratin, histones, avian beta defensins, ovocalyxin-36, apolipoproteins, protocadherin, chondroitin sulfate, ovotransferrin, hyaluronic acid, and sialic acid as well as various amino acids. Recently, ES has been widely used in industry, agriculture, food, and medical fields. The potential of ES in the medical field is interesting to discuss, especially in relation to tissue repair. Efforts to reduce the prevalence of wounds that generally originate from acute wounds but become chronic due to various factors that are neglected in their management. In particular, this review will describe the benefits of ES content in repairing body tissues. ES-derived active ingredients such as CaCO3, brushite, and hydroxyapatite exhibit osteoconductive properties that promote bone regeneration. Calcium ions can increase insulin and leptin sensitivity in the liver and can induce repair of acute kidney injury. Meanwhile, ESM contributes positively to neural tissue repair and plays an important role in wound healing, response to external stimuli, defense response, inflammatory response, cell-substrate adhesion, promoting cell growth, migration, differentiation, and tissue remodeling.

Tubulovascular protection from protease-activated receptor-1 depletion during AKI-to-CKD transition.

Thromboembolic events are prevalent in chronic kidney disease (CKD) patients due to increased thrombin generation leading to a hypercoagulable state. We previously demonstrated that inhibition of protease-activated receptor-1 (PAR-1) by vorapaxar reduces kidney fibrosis. We used an animal model of unilateral ischemia-reperfusion injury-induced CKD to explore the tubulovascular crosstalk mechanisms of PAR-1 in acute kidney injury (AKI)-to-CKD transition. During the early phase of AKI, PAR-1-deficient mice exhibited reduced kidney inflammation, vascular injury, and preserved endothelial integrity and capillary permeability. During the transition phase to CKD, PAR-1 deficiency preserved kidney function and diminished tubulointerstitial fibrosis via downregulated transforming growth factor-β/Smad signaling. Maladaptive repair in the microvasculature after AKI further exacerbated focal hypoxia with capillary rarefaction, which was rescued by stabilization of hypoxia-inducible factor and increased tubular vascular endothelial growth factor A in PAR-1-deficient mice. Chronic inflammation was also prevented with reduced kidney infiltration by both M1- and M2-polarized macrophages. In thrombin-induced human dermal microvascular endothelial cells (HDMECs), PAR-1 mediated vascular injury through activation of NF-κB and ERK MAPK pathways. Gene silencing of PAR-1 exerted microvascular protection via a tubulovascular crosstalk mechanism during hypoxia in HDMECs. Finally, pharmacologic blockade of PAR-1 with vorapaxar improved kidney morphology, promoted vascular regenerative capacity, and reduced inflammation and fibrosis depending on the time of initiation. Our findings elucidate a detrimental role of PAR-1 in vascular dysfunction and profibrotic responses upon tissue injury during AKI-to-CKD transition and provide an attractive therapeutic strategy for post-injury repair in AKI.

GDF11 Improves Ischemia-Reperfusion-Induced Acute Kidney Injury via Regulating Macrophage M1/M2 Polarization

Introduction: Acute kidney injury (AKI) is a clinical emergency caused by the rapid decline of renal function caused by various etiologies. Growth differentiation factor 11 (GDF11) can promote renal tubular regeneration and improve kidney function in AKI, but the specific mechanism remains unclear. Herein, we investigated the effect and mechanisms of GDF11 in ameliorating AKI induced by ischemia-reperfusion (I/R). Methods: An animal model of AKI was established by I/R method, and the changes of serum urea nitrogen and creatinine were measured to evaluate the AKI. Enzyme-linked immunosorbent assay (ELISA) was used to measure cytokines, malondialdehyde, superoxide dismutase, nitric oxide synthase, and arginase 1 levels. Flow cytometry was used to count the M1/M2 macrophages. IHC, WB, and q-PCR experiments were used to evaluate the expression of GDF11. Results: The changes in serum levels of urea nitrogen and creatinine after I/R suggest that an animal model of AKI induced by I/R was successfully established. AKI caused by I/R significantly changed the M1/M2 macrophage polarization balance, with an increase in M2 being significantly higher than M1 as well as increased oxidative stress. Treatment with GDF11 after I/R significantly increased the differentiation of M2 cells and inhibited the differentiation of M1 macrophages, as well as decreased oxidative stress. Conclusion: GDF11 can promote the repair of AKI caused by I/R by regulating the balance of M1/M2 polarization in macrophages and oxidative stress.

Deletion of Antigen-Presenting Cells in Lipopolysaccharide-Induced Acute Kidney Injury (AKI) Affects the Exacerbation and Repair in AKI.

The pathogenesis of acute kidney injury (AKI) is complex and involves various immune and inflammatory responses. Antigen-presenting cells such as macrophages and dendritic cells (DCs) were recently reported to have diverse functions in AKI depending on the pathogenesis and disease phase. Herein, we intraperitoneally administered liposomal clodronate (LC) to lipopoly-saccharide (LPS)-induced AKI model mice in order to deplete antigen-presenting cells (e.g., macrophages and DCs). After the LPS injection, the mice were divided into LC-treated (LPS + LC) and saline-treated groups (LPS), and the immune responses of macrophages and DCs in the acute and recovery phases were evaluated. The LPS + LC-treated group exhibited significantly suppressed renal macrophages and DC infiltration at 18 h and improved survival at 120 h after LPS injection. Via the depletion of macrophages and DC infiltrations, the serum and renal tissue inflammatory cytokines/chemokines were suppressed at 18 h and reversed at 120 h. Tubular kidney injury molecule-1 expression was decreased at 18 h and increased at 120 h. These findings indicate that LC administration suppressed tubular and interstitial injury in the acute phase of AKI and affected delayed tissue repair in the recovery phase. They are important for understanding innate and acquired immune responses in the therapeutic strategy for LPS-induced AKI.

Sex differences in resilience to ferroptosis underlie sexual dimorphism in kidney injury and repair.

In both humans and mice, repair of acute kidney injury is worse in males than in females. Here, we provide evidence that this sexual dimorphism results from sex differences in ferroptosis, an iron-dependent, lipid-peroxidation-driven regulated cell death. Using genetic and single-cell transcriptomic approaches in mice, we report that female sex confers striking protection against ferroptosis, which was experimentally induced in proximal tubular (PT) cells by deleting glutathione peroxidase 4 (Gpx4). Single-cell transcriptomic analyses further identify the NFE2-related factor 2 (NRF2) antioxidant protective pathway as a female resilience mechanism against ferroptosis. Genetic inhibition and pharmacological activation studies show that NRF2 controls PT cell fate and plasticity by regulating ferroptosis. Importantly, pharmacological NRF2 activation protects male PT cells from ferroptosis and improves cellular plasticity as in females. Our data highlight NRF2 as a potential therapeutic target to prevent failed renal repair after acute kidney injury in both sexes by modulating cellular plasticity.

MiR-21-5p in extracellular vesicles obtained from adipose tissue-derived stromal cells facilitates tubular epithelial cell repair in acute kidney injury

Background aimsAcute kidney injury (AKI) is often associated with poor patient outcomes. Extracellular vesicles (EVs) have a marked therapeutic effect on renal recovery. This study sought to explore the functional mechanism of EVs from adipose tissue-derived stromal cells (ADSCs) in tubular epithelial cell (TEC) repair in AKI. MethodsADSCs were cultured and EVs were isolated and identified. In vivo and in vitro AKI models were established using lipopolysaccharide (LPS). ResultsEVs increased human kidney 2 (HK-2) cell viability; decreased terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells and levels of kidney injury molecule 1, cleaved caspase-1, apoptosis-associated speck-like protein containing a CARD, gasdermin D-N, IL-18 and IL-1β; and elevated pro-caspase-1. EVs carried miR-21-5p into LPS-induced HK-2 cells. Silencing miR-21-5p partly eliminated the ability of EVs to suppress HK-2 cell pyroptosis and inflammation. miR-21-5p targeted toll-like receptor 4 (TLR4) and inhibited TEC pyroptosis and inflammation after AKI by inhibiting TLR4. TLR4 overexpression blocked the inhibitory effects of EVs on TEC pyroptosis and inflammation. EVs suppressed the nuclear factor-κB/NOD-like receptor family pyrin domain-containing 3 (NF-κB/NLRP3) pathway via miR-21-5p/TLR4. Finally, AKI mouse models were established and in vivo assays verified that ADSC-EVs reduced TEC pyroptosis and inflammatory response and potentiated cell repair by mediating miR-21-5p in AKI mice. ConclusionsADSC-EVs inhibited inflammation and TEC pyroptosis and promoted TEC repair in AKI by mediating miR-21-5p to target TLR4 and inhibiting the NF-κB/NLRP3 pathway.

PTEN-induced kinase 1 enhances the reparative effects of bone marrow mesenchymal stromal cells on mice with renal ischaemia/reperfusion-induced acute kidney injury

Acute kidney injury (AKI) is a common severe acute syndrome caused by multiple factors and is characterized by a rapid decline in renal function during a short period. Bone marrow mesenchymal stromal cells (BMSCs) are effective in treating AKI. However, the mechanism of their beneficial effects remains unclear. PTEN-induced kinase 1 (PINK1) may play an important role in kidney tissue repair. In this study, we explored the effect of PINK1 overexpression on enhancing BMSC-mediated repair of AKI. In this study, ischaemia/reperfusion-induced AKI (IRI-AKI) in mice and a hypoxia-reoxygenation model in cells were established, and the indices were examined by pathology and immunology experiments. After ischaemia/reperfusion, PINK1 overexpression reduced apoptosis in injured kidney tissue cell, decreased T lymphocyte infiltration, increased macrophage infiltration, and alleviated the inflammatory response. PINK1 relieved the stress response of BMSCs and renal tubular epithelial cells (RTECs), reduced apoptosis, altered the release of inflammatory factors, and reduced the proliferation of peripheral blood mononuclear cells (PBMCs). In conclusion, BMSCs and RTECs undergo stress responses in response to hypoxia, inflammation and other conditions, and overexpressing PINK1 in BMSCs could enhance their ability to resist these stress reactions. Furthermore, PINK1 overexpression can regulate the distribution of immune cells and improve the inflammatory response. The regulation of mitochondrial autophagy during IRI-AKI maintains mitochondrial homeostasis and protects renal function. The results of this study provide new strategies and experimental evidence for BMSC-mediated repair of IRI-AKI.

Hypoxia-inducible factor protects against acute kidney injury via the Wnt/β-catenin signaling pathway.

Promoting adaptive repair in acute kidney injury (AKI) is an effective strategy to prevent the progression from AKI to chronic kidney disease. However, the mechanisms involved in renal repair after AKI remain unclear. In this study, we investigated the role of hypoxia-inducible factor (HIF), an important regulator of ischemic and hypoxic injury, in AKI during the repair phase. We established mouse models of ischemia-reperfusion injury-induced AKI with adaptive repair or maladaptive repair. We found that after injury, activation of HIF in the adaptive repair group was rapid, whereas in the maladaptive repair group HIF activation was relatively delayed, and its expression was significantly lower than that in the adaptive repair group during the early repair phase. To further investigate the mechanism of HIF, we regulated the expression of HIF-1α and HIF-2α in HK-2 cells and EA.hy926 cells, respectively. Silencing HIF expression reduced proliferation and increased apoptosis in cells injured by hypoxia/reoxygenation. Self-healing ability was further reduced due to the downregulation of HIF. Moreover, HIF overexpression had the opposite effect. HIF increased the expression of β-catenin and its downstream target genes. Activation of Wnt/β-catenin by the small-molecule activator SKL2001 mitigated the damaging effect of HIF knockdown, whereas blockade of β-catenin with the inhibitor IWR-1-endo reduced the protective effects of HIF. In conclusion, HIF, which is highly expressed in the early stage after AKI, promotes renal repair by interacting with the Wnt/β-catenin signaling pathway.NEW & NOTEWORTHY We investigated the role of hypoxia-inducible factor (HIF) in acute kidney injury in vivo and in vitro. Expression of HIF in the adaptive repair group was more rapid and sufficient than that in the maladaptive repair group during the early repair phase. HK-2 and EA.hy926 cells treated with hypoxia/reoxygenation were used to elucidate the cross talk between HIF and the Wnt/β-catenin signaling pathway by which HIF played a renoprotective role in acute kidney injury.

Roxadustat (FG-4592) Facilitates Recovery From Renal Damage by Ameliorating Mitochondrial Dysfunction Induced by Folic Acid.

Incomplete recovery from acute kidney injury induced by folic acid is a major risk factor for progression to chronic kidney disease. Mitochondrial dysfunction has been considered a crucial contributor to maladaptive repair in acute kidney injury. Treatment with FG-4592, an inhibitor of hypoxia inducible factor prolyl-hydroxylase, is emerging as a new approach to attenuate renal damage; however, the underlying mechanism has not been fully elucidated. The current research demonstrated the protective effect of FG-4592 against renal dysfunction and histopathological damage on the 7th day after FA administration. FG-4592 accelerated tubular repair by promoting tubular cell regeneration, as indicated by increased proliferation of cell nuclear antigen-positive tubular cells, and facilitated structural integrity, as reflected by up-regulation of the epithelial inter-cellular tight junction molecule occludin-1 and the adherens junction molecule E-cadherin. Furthermore, FG-4592 ameliorated tubular functional recovery by restoring the function-related proteins aquaporin1, aquaporin2, and sodium chloride cotransporter. Specifically, FG-4592 pretreatment inhibited hypoxia inducible factor-1α activation on the 7th day after folic acid injection, which ameliorated ultrastructural abnormalities, promoted ATP production, and attenuated excessive reactive oxygen species production both in renal tissue and mitochondria. This was mainly mediated by balancing of mitochondrial dynamics, as indicated by down-regulation of mitochondrial fission 1 and dynamin-related protein 1 as well as up-regulation of mitofusin 1 and optic atrophy 1. Moreover, FG-4592 pretreatment attenuated renal tubular epithelial cell death, kidney inflammation, and subsequent interstitial fibrosis. In vitro, TNF-α-induced HK-2 cells injury could be ameliorated by FG-4592 pretreatment. In summary, our findings support the protective effect of FG-4592 against folic acid-induced mitochondrial dysfunction; therefore, FG-4592 treatment can be used as a useful strategy to facilitate tubular repair and mitigate acute kidney injury progression.

SIRT3 deficiency exacerbates early-stage fibrosis after ischaemia-reperfusion-induced AKI

BackgroundSirtuin 3 (SIRT3) is a crucial regulator of mitochondrial function and is associated with injury and repair in acute kidney injury (AKI). To investigate whether mitochondrial damage and early renal fibrosis are associated with decreased renal SIRT3 levels, we established an in vivo model. MethodsIn vivo, we established ischaemia-reperfusion-induced AKI (IR-AKI) models in wild-type (WT) and SIRT3-knockout (SIRT3-KO) mice. Serum creatinine (Scr) and blood urea nitrogen (BUN) were measured by an automatic biochemical analyser, and renal pathological changes were examined by haematoxylin and eosin (HE) staining. Renal fibrosis in mice was assessed by Masson's trichrome staining. The expression of SIRT3, renal fibrosis-related markers (FN and α-SMA), and mitochondrial markers (DRP1, FIS1, OPA1, and MFN1) was measured by Western blotting. Morphological changes in mitochondria in renal tubular epithelial cells were analysed by transmission electron microscopy (TEM). ResultsThe levels of Scr and BUN were elevated with severe renal pathological damage in the IR-AKI model, especially in SIRT3-KO mice. In the IR-AKI model, the obvious increases in FN and α-SMA protein levels suggested that there was severe fibrosis in the kidney tissue, OPA1 and MFN1 protein levels were reduced while DRP1 and FIS1 protein levels were greatly increased. TEM photomicrographs showed that mitochondrial fragmentation was increased in the renal tubular epithelial cells of mice with IR injury. SIRT3-KO mice exhibited exacerbated changes. ConclusionOur findings indicate that SIRT3 plays a significant role in early-stage fibrosis after IR-AKI by regulating mitochondrial dynamics and that SIRT3 deficiency exacerbates renal dysfunction and renal fibrosis.

A supramolecular hydrogel based on the combination of YIGSR and RGD enhances mesenchymal stem cells paracrine function via integrin α2β1 and PI3K/AKT signaling pathway for acute kidney injury therapy

Mesenchymal stem cell (MSC) transplantation has emerged as a promising strategy for the treatment of acute kidney injury (AKI). However, MSC-based therapies are limited by their low cell retention and reduced survival rates at the site of injury. YIGSR (Tyr-Ile-Gly-Ser-Arg) and RGD (Arg-Gly-Asp) peptides derived from the integral components of the extracellular matrix, laminin, and fibronectin, can provide structural support and a suitable microenvironment for MSCs. As their individual effect is inadequate, we conjugated the YIGSR and RGD peptides to form a novel YIGSRGD peptide. We speculated that the conjugated peptide could be more efficient in promoting the survival and therapeutic efficacy of MSCs than the individual peptides. Moreover, to provide a conducive microenvironment for MSCs, we covalently linked biocompatible biotin to a D-amino acid (DF), which conferred resistance against enzymatic degradation. This increased the stability of YIGSRGD as a functional scaffold and led to the development of a novel, bioactive and biocompatible Biotin-DFYIGSRGD hydrogel. The survival of MSCs was monitored using bioluminescence imaging. The roles of the integrin α2β1 and PI3K/AKT pathway in the secretion of important curative cytokines, such as, HGF, VEGFa, and IL-10 were elucidated by silencing them. Results showed that the Biotin-DFYIGSRGD hydrogel prolonged survival and augmented the paracrine function of MSCs, thereby enhancing their anti-apoptotic and anti-inflammatory effects on the damaged kidney. These findings indicate that the proposed hydrogel can enhance the therapeutic effects and applicability of MSCs via the YIGSRGD/integrin α2β1/PI3K/AKT axis to promote kidney repair in AKI.

POS-064 DcR2 mediates the maladaptive repair of acute kidney injury by regulating the synthesis the β-hydroxybutyrate

Acute kidney injury (AKI) is a common clinical emergency and critical illness, and has a high mortality rate among hospitalized patients. The repair and regeneration of renal tubular cells determine the prognosis of AKI. Our previous study found that decoy receptor 2 (DcR2), a trans-membrane receptor of tumor necrosis factor-related apoptosis inducing ligand (TRAIL), was specifically expressed renal tubules and did not have the ability of proliferation in AKI, suggesting DcR2 may be associated with regeneration and repair of tubular cells. This study aims to investigate the role and mechanism of DcR2-positive tubular cells in the repair of AKI. The DcR2-GFP lineage trace mice,KSP-creDcR2f/fmice (Distal tubular DcR2 Conditional Knockout CKO) mice and GGT1-creDcR2f/f(proximal tubular DcR2 Conditional Knockout CKO) mice and Ischemia-Reperfusion (I/R) Injury models were constructed. The models were divided into moderated (ischemia 25min) and severe (ischemia 35min) injury. Light microscopic examination of paraffin-embedded sections stained with haematoxylin and eosin, periodic acid–Schiff stain and Masson stain. Confocal analysis the co-expression of DcR-GFP and proximal tubular markers(AQP1, Villin), distal markers (AQP2), failed repair markers (Vcam1, Dcdc2), proliferative markers (Ki-67, Edu, PCNA), Kim1, differentiated markers (pax2, sox9, six2), senescent markers (P16, P21, SA-β-gal), senescent phenotype (IL-6, TGF-β1) and fibrotic markers (a-SMA, collagen I, Fibronectin). And wild type (WT) mice and DcR2 CKO mice were used to compare the degree of kidney injury, renal function and tubular repair after I/R injury. Furthermore, quantitative proteomics and bioinformatics analyzed the downstream molecules of DcR2 in renal tissues from WT-AKI and CKO-AKI, and validated studied were done. The DcR2-GFP were mainly expressed proximal tubular cells in AKI. DcR2-GFP positive cells were co-expressed failed repair markers, senescent markers and co-localization with fibrotic markers. And DcR2-GFP positive cells were not expressed Kim1, proliferative markers and differentiated markers, suggesting that DcR2-positve tubules were maladaptive repair cells. The levels of Scr, BUN and urinary DcR2 and renal acute and chronic injury scores were significantly lower inGGT1-creDcR2f/f-AKI than that of WT-AKI. Meanwhile, the area of renal fibrosis and fibrotic markers expression was decreased inGGT1-creDcR2f/fmice compared with WT. However, the above phenomenon of KSP-creDcR2f/f–AKI were not obviously improved. These results suggested that proximal tubular DcR2 gene knockout alleviated kidney injury and promote tubular repair. Additionally, quantitative proteomics and validated studies showed HMGCS2, a key enzyme for ketone synthesis, was increased in GGT1-creDcR2f/fmice compared with WT. And the levels of urinary and serum β-hydroxybutyrate were higher inGGT1-creDcR2f/fmice, suggesting DcR2 affects the synthesis of β-hydroxybutyrate through regulating the expression of HMGCS2. DcR2-positive cells were failed-repair tubules in AKI. And DcR2 promotes maladaptive repair of tubular cells through regulating the expression of HMGCS2 and affects the synthesis of β-hydroxybutyrate, suggesting that DcR2 may be a potential intervention target during the progression of AKI, and β-hydroxybutyrate play a critical role in the repair of AKI.

The Hippo pathway and its correlation with acute kidney injury.

Acute kidney injury (AKI) is a significant clinical complication with a substantial impact on morbidity and mortality, for which therapeutic options remain limited. The Hippo signaling pathway is an evolutionarily conserved pathway implicated in cell proliferation, dedifferentiation, and apoptosis via phosphorylation and inactivation of its downstream effectors Yes-associated protein (YAP)/ transcriptional co-activator with PDZ-binding motif (TAZ). Recent studies have revealed that the Hippo pathway plays a pivotal role in the pathogenesis and repair of AKI. The Hippo pathway can mediate renal dysfunction through modulation of mitochondrial apoptosis under AKI conditions. Transient activation of YAP/TAZ in the acute phase of AKI may benefit renal recovery and regeneration, whereas persistent activation of YAP/TAZ in severe AKI may lead to maladaptive repair and transition to chronic kidney disease. This review aims to summarize recent findings on the associations between the Hippo pathway and AKI and to identify new therapeutic targets and strategies for AKI.

High salt exacerbates acute kidney injury by disturbing the activation of CD5L/apoptosis inhibitor of macrophage (AIM) protein.

The influence of excess salt intake on acute kidney injury (AKI) has not been examined precisely except for some clinical data, unlike in chronic kidney disease. Here, we addressed the influence of high salt (HS) on AKI and its underlying mechanisms in terms of the activity of circulating apoptosis inhibitor of macrophage (AIM, also called CD5L) protein, a facilitator of AKI repair. HS loading in mice subjected to ischemia/reperfusion (IR) resulted in high mortality with advanced renal tubular obstruction and marked exacerbation in biomarkers of proximal renal tubular damage. This AKI exacerbation appeared to be caused mainly by the reduced AIM dissociation from IgM pentamer in serum, as IgM-free AIM is indispensable for the removal of intratubular debris to facilitate AKI repair. Injection of recombinant AIM (rAIM) ameliorated the AKI induced by IR/HS, dramatically improving the tubular damage and mouse survival. The repair of lethal AKI by AIM was dependent on AIM/ kidney injury molecule-1 (KIM-1) axis, as rAIM injection was not effective in KIM-1 deficient mice. Our results demonstrate that the inhibition of AIM dissociation from IgM is an important reason for the exacerbation of AKI by HS, that AIM is a strong therapeutic tool for severe AKI.

Bone marrow derived mesenchymal stem cells pretreated with erythropoietin accelerate the repair of acute kidney injury

BackgroundMesenchymal stem cells (MSCs) represent a promising treatment option for acute kidney injury (AKI). The main drawbacks of MSCs therapy, including the lack of specific homing after systemic infusion and early cell death in the inflammatory microenvironment, directly affect the therapeutic efficacy of MSCs. Erythropoietin (EPO)-preconditioning of MSCs promotes their therapeutic effect, however, the underlying mechanism remains unknown. In this study, we sought to investigate the efficacy and mechanism of EPO in bone marrow derived mesenchymal stem cells (BMSCs) for AKI treatment.ResultsWe found that incubation of BMSCs with ischemia/reperfusion(I/R)-induced AKI kidney homogenate supernatant (KHS) caused apoptosis in BMSCs, which was decreased by EPO pretreatment, indicating that EPO protected the cells from apoptosis. Further, we showed that EPO up-regulated silent information regulator 1 (SIRT1) and Bcl-2 expression and down-regulated p53 expression. This effect was partially reversed by SIRT1 siRNA intervention. The anti-apoptotic effect of EPO in pretreated BMSCs may be mediated through the SIRT1 pathway. In a rat AKI model, 24 h after intravenous infusion, GFP-BMSCs were predominantly located in the lungs. However, EPO pretreatment reduced the lung entrapment of BMSCs and increased their distribution in the target organs. AKI rats infused with EPO-BMSCs had significantly lower levels of serum IL-1β and TNF-α, and a significantly higher level of IL-10 as compared to rats infused with untreated BMSCs. The administration of EPO-BMSCs after reperfusion reduced serum creatinine, blood urea nitrogen, and pathological scores in I/R-AKI rats more effectively than BMSCs treatment did.ConclusionsOur data suggest that EPO pretreatment enhances the efficacy of BMSCs to improve the renal function and pathological presentation of I/R-AKI rats.

The Yin and Yang of Alarmins in Regulation of Acute Kidney Injury.

Acute kidney injury (AKI) is a major clinical burden affecting 20 to 50% of hospitalized and intensive care patients. Irrespective of the initiating factors, the immune system plays a major role in amplifying the disease pathogenesis with certain immune cells contributing to renal damage, whereas others offer protection and facilitate recovery. Alarmins are small molecules and proteins that include granulysins, high-mobility group box 1 protein, interleukin (IL)-1α, IL-16, IL-33, heat shock proteins, the Ca++ binding S100 proteins, adenosine triphosphate, and uric acid. Alarmins are mostly intracellular molecules, and their release to the extracellular milieu signals cellular stress or damage, generally leading to the recruitment of the cells of the immune system. Early studies indicated a pro-inflammatory role for the alarmins by contributing to immune-system dysregulation and worsening of AKI. However, recent developments demonstrate anti-inflammatory mechanisms of certain alarmins or alarmin-sensing receptors, which may participate in the prevention, resolution, and repair of AKI. This dual function of alarmins is intriguing and has confounded the role of alarmins in AKI. In this study, we review the contribution of various alarmins to the pathogenesis of AKI in experimental and clinical studies. We also analyze the approaches for the therapeutic utilization of alarmins for AKI.