Ischemic Renal Injury Research Articles

Clinical and Pathological Features of Renal Presentations in Polycythemia Vera

BackgroundPolycythemia vera (PV) is a common type of Philadelphia chromosome-negative chronic myeloproliferative disorder. PV-associated kidney disease is rarely reported and remains poorly understood. It has been observed that chronic kidney disease could be a risk factor for poor prognosis in PV. MethodsWe retrospectively analyzed the clinicopathological features of renal presentations in eight patients with confirmed PV-associated kidney disease. ResultsThe eight patients were 6 males and 2 females, with a mean age of 46.4 ± 16.8 years. Six patients had a history of PV, with a duration range 0.5–16 years. The other two patients were newly diagnosed with PV simultaneously with glomerular disease. Seven patients conducted a JAK2 V617F mutation test, with a positive result in five. Proteinuria and renal dysfunction were the patients' main complaints, with only one having nephrotic syndrome and three having microscopic hematuria. The level of proteinuria ranged from 0.52–10.96 g/day. Three patients had advanced chronic kidney disease (CKD), two in stage 3b and one in stage 4, but only one patient had anemia. Three patients had monoclonal immunoglobulinemia, one patient with immunoglobulin (Ig) G kappa plus light chain lambda, one patient with IgG kappa, and one patient with IgG lambda. Five patients underwent a renal biopsy. The pathological diagnosis was IgA nephropathy in three, non-IgA mesangial proliferative glomerulopathy in one, and glomerular hypertrophy with ischemic renal injury in one patient. Glomerular ischemia, ischemic shrinkage, focal segmental sclerosis, and glomerulomegaly were common pathological features. Glomerular crescents and endocapillary proliferation were also observed. All patients were administered hydroxyurea, and seven were administered renin-angiotensin system inhibitors. During follow-up, one patient with uncontrolled PV developed secondary myelofibrosis and died, three patients were lost to follow-up, and four patients remained alive with CKD. ConclusionsPatients with untreated or uncontrolled PV could have massive proteinuria and advanced CKD, pathologically showing ischemic, sclerosing glomerular lesions with hypercellurity, glomerular crescents and endocapillary proliferation. IgA nephropathy was most commonly diagnosed. These findings deserve attention because early screening and effective control of PV may benefit the long-term kidney prognosis.

Angiotensin II type 2 receptor agonist, compound 21, prevents tubular epithelial cell damage caused by renal ischemia

During ischemic acute kidney injury (AKI), loss of cytoskeletal integrity and disruption of intercellular junctions are rapid events in response to ATP depletion. Angiotensin II type 2 receptor (AT2R) is overexpressed in injury situations and its stimulation by angiotensin II (AngII) is related to beneficial renal effects. Its role on ischemic AKI has not been deeply studied. The aim of the present study was to investigate whether pretreatment with the AT2R agonist, C21, prevents ischemic renal epithelial cell injury. Studies in a model of 40 min of renal ischemia followed by 24 h of reperfusion (IR) in rats demonstrated that C21 pretreatment attenuated renal dysfunction and induced better preservation of tubular architecture. In addition, we studied the expression of Rho GTPases, RhoA and Cdc42, since they are key proteins in the regulation of the actin cytoskeleton and the stability of epithelial intercellular junctions. IR downregulated RhoA and Cdc42 abundance in rat kidneys. C21 pretreatment prevented RhoA reduction and increased Cdc42 abundance compared to controls. We also used an in vitro model of ATP depletion in MDCK cells grown on filter support. Using immunofluorescence we observed that in MDCK cells, C21 pretreatment prevented the ATP depletion-induced reduction of actin in brush border microvilli and in stress fibers. Moreover, C21 prevented membrane E-cadherin reduction, and RhoA and Cdc42 downregulation. The present study describes for the first time a renoprotective effect of the AT2R agonist, C21, against AKI, and provides evidence supporting that stimulation of AT2R triggers cytoprotective mechanisms against an ischemic event.

Assessment of the Nephroprotective Properties of the Erythropoietin Mimetic Peptide and Infliximab in Kidney Ischemia-Reperfusion Injury in Rats.

Chronic kidney disease (CKD) or acute kidney injury (AKI) causes impaired kidney function, leading to cognitive impairment, neuropathy, and cerebrovascular disease. Due to kidney damage, toxinsstay in thebloodrather thanleavingthebodythrough the urine, and brain function is affected by kidney-brain interaction. The present study aimed to investigate the protective effects of erythropoietin mimetic peptide (pHBSP) and infliximab on ischemic renal reperfusion injury. The experiment was performed on 70 white male Wistar laboratory rats which received recombinant erythropoietin, pHBSP, and infliximab. Under anesthesia, traumatic vascular clamps were applied to the left renal pedicle for 40 min, and nephrectomy was performed on the right. Functional tests and laboratory tests were performed 5 min and 24 h after the reperfusion. Thereafter, 24 h after the surgery, the plasma creatinine and urea levels in the sham-operated animals were obtained at 45.9±0.8 mmol/L and 6.7±0.2 mmol/L, respectively. Plasma creatinine and urea levels in the control group animals were 102.63±3.6 mmol/L and 21.80±1.29 mmol/L, respectively. The administration of pHBSP and infliximab to the animals with ischemia-reperfusion kidney injury has a pronounced nephroprotective effect, as compared to erythropoietin. There was a significant decrease in blood levels of creatinine and urea, improvement of microcirculation in the kidney, normalization of glomerular filtration rate, and fractional sodium excretion. The results of the study demonstrated pointed to the prospects of pHBSP and infliximab administration in ischemia-reperfusion kidney injury and justified the feasibility of further research in this field.

Value of point-of-care neutrophil gelatinase associated lipocalin in early diagnosis of acute kidney injury in patients with left ventricular systolic dysfunction after coronary angiography

Background: Increased neutrophil gelatinase-associated lipocalin (NGAL) levels are associated with toxic or ischemic renal injury. Objective: This study aimed to assess the usefulness of serial NGAL measurements with a point-of-care assay in patients with left ventricular systolic dysfunction (LVSD) for earlier detection of contrast-induced nephropathy (CIN). Materials and methods: A total of 84 patients with LVSD patients referred for coronary angiography were consecutively enrolled in the study. The study population was divided into two groups as the CIN and the non-CIN groups according to the CIN's determination. The serum creatinine levels were calculated 24 h before the procedure and at the 48th and 72nd h after the cardiac catheterization. The plasma NGAL concentration was measured before and at 4 and 24 h after the cardiac catheterization. Results: Baseline and serial NGAL levels were significantly higher in patients with CIN compared to the patients without CIN. NGAL 24th h levels after the index procedure were found to be an independent and significant predictor of CIN in multivariate analysis. Conclusions: Serial point-of-care NGAL measurements might help earlier detection of CIN in patients with heart failure after coronary angiography.

Renal denervation alleviates renal ischemic reperfusion injury-induced acute and chronic kidney injury in rats partly by modulating miRNAs.

Renal denervation (RDN) has been used to promote kidney injury repair, whereas miRNAs have been found to be involved in the pathophysiology of renal injury. However, the miRNA alterations that occur after RDN and the related protective mechanisms remain to be determined. Renal ischemic reperfusion injury (IRI) rat model was established and RDN was performed. Animals were killed at 24h and 2weeks following the operation. Tyrosine hydroxylase (TH) levels, renal function, tubular cell apoptosis and histological sections were examined at 24h, whereas renal fibrosis and capillary vessels were assessed at 2weeks. Furthermore, the expression of miRNAs in the injured kidney was determined using micro-array and the target genes were analyzed. We found that TH was eliminated and that renal function was improved in the denervation group at 24h. RDN reduced tubular cell apoptosis and mitigated the histological lesion. Furthermore, an increase of capillary vessel density and reduction of renal fibrosis were observed after 2weeks. Moreover, the numbers of miRNAs were up-regulated after RDN treatment, and the miRNAs targeted pro-angiogenic, anti-fibrotic and inflammatory pathways. RDN is a reliable method for alleviating IRI-induced acute and chronic kidney injury, and modulating the miRNA-related pro-angiogenic, anti-fibrotic or inflammatory pathways involved in this process.

Progressive Cellular Senescence Mediates Renal Dysfunction in Ischemic Nephropathy.

Peripheral vascular diseases may induce chronic ischemia and cellular injury distal to the arterial obstruction. Cellular senescence involves proliferation arrest in response to stress, which can damage neighboring cells. Renal artery stenosis (RAS) induces stenotic-kidney dysfunction and injury, but whether these arise from cellular senescenceand their temporal pattern remain unknown. Chronic renal ischemia was induced in transgenic INK-ATTAC and wild type C57BL/6 mice by unilateral RAS, and kidney function (in vivo micro-MRI) and tissue damage were assessed. Mouse healthy and stenotic kidneys were analyzed using unbiased single-cell RNA-sequencing. To demonstrate translational relevance, cellular senescence was studied in human stenotic kidneys. Using intraperitoneal AP20187 injections starting 1, 2, or 4 weeks after RAS, selective clearance of cells highly expressing p16Ink4a attenuated cellular senescence and improved stenotic-kidney function; however, starting treatment immediately after RAS induction was unsuccessful. Broader clearance of senescent cells, using the oral senolytic combination dasatinib and quercetin, in C57BL/6 RAS mice was more effective in clearing cells positive for p21 (Cdkn1a) and alleviating renal dysfunction and damage. Unbiased, single-cell RNA sequencing in freshly dissociated cells from healthy and stenotic mouse kidneys identified stenotic-kidney epithelial cells undergoing both mesenchymal transition and senescence. As in mice, injured human stenotic kidneys exhibited cellular senescence, suggesting this process is conserved. Maladaptive tubular cell senescence, involving upregulated p16 (Cdkn2a), p19 (Cdkn2d), and p21 (Cdkn1a) expression, is associated with renal dysfunction and injury in chronic ischemia. These findings support development of senolytic strategies to delay chronic ischemic renal injury.

Sirtuin 5 depletion impairs mitochondrial function in human proximal tubular epithelial cells

Ischemia is a major cause of kidney damage. Proximal tubular epithelial cells (PTECs) are highly susceptible to ischemic insults that frequently cause acute kidney injury (AKI), a potentially life-threatening condition with high mortality. Accumulating evidence has identified altered mitochondrial function as a central pathologic feature of AKI. The mitochondrial NAD+-dependent enzyme sirtuin 5 (SIRT5) is a key regulator of mitochondrial form and function, but its role in ischemic renal injury (IRI) is unknown. SIRT5 expression was increased in murine PTECs after IRI in vivo and in human PTECs (hPTECs) exposed to an oxygen/nutrient deprivation (OND) model of IRI in vitro. SIRT5-depletion impaired ATP production, reduced mitochondrial membrane potential, and provoked mitochondrial fragmentation in hPTECs. Moreover, SIRT5 RNAi exacerbated OND-induced mitochondrial bioenergetic dysfunction and swelling, and increased degradation by mitophagy. These findings suggest SIRT5 is required for normal mitochondrial function in hPTECs and indicate a potentially important role for the enzyme in the regulation of mitochondrial biology in ischemia.

Preexisting heart failure with reduced ejection fraction attenuates renal fibrosis after ischemia reperfusion via sympathetic activation

Although chronic heart failure is clinically associated with acute kidney injury (AKI), the precise mechanism that connects kidney and heart remains unknown. Here, we elucidate the effect of pre-existing heart failure with reduced ejection fraction (HFrEF) on kidney via sympathetic activity, using the combining models of transverse aortic constriction (TAC) and unilateral renal ischemia reperfusion (IR). The evaluation of acute (24 h) and chronic (2 weeks) phases of renal injury following IR 8 weeks after TAC in C57BL/6 mice revealed that the development of renal fibrosis in chronic phase was significantly attenuated in TAC mice, but not in non-TAC mice, whereas no impact of pre-existing heart failure was observed in acute phase of renal IR. Expression of transforming growth factor-β, monocyte chemoattractant protein-1, and macrophage infiltration were significantly reduced in TAC mice. Lastly, to investigate the effect of sympathetic nerve activity, we performed renal sympathetic denervation two days prior to renal IR, which abrogated attenuation of renal fibrosis in TAC mice. Collectively, we demonstrate the protective effect of pre-existing HFrEF on long-term renal ischemic injury. Renal sympathetic nerve may contribute to this protection; however, further studies are needed to fully clarify the comprehensive mechanisms associated with attenuated renal fibrosis and pre-existing HFrEF.

Deletion of Myeloid Interferon Regulatory Factor 4 (Irf4) in Mouse Model Protects against Kidney Fibrosis after Ischemic Injury by Decreased Macrophage Recruitment and Activation.

AKI is characterized by abrupt and reversible kidney dysfunction, and incomplete recovery leads to chronic kidney injury. Previous studies by us and others have indicated that macrophage infiltration and polarization play key roles in recovery from AKI. The role in AKI recovery played by IFN regulatory factor 4 (IRF4), a mediator of polarization of macrophages to the M2 phenotype, is unclear. We used mice with myeloid or macrophage cell-specific deletion of Irf4 (MΦ Irf4-/- ) to evaluate Irf4's role in renal macrophage polarization and development of fibrosis after severe AKI. Surprisingly, although macrophage Irf4 deletion had a minimal effect on early renal functional recovery from AKI, it resulted in decreased renal fibrosis 4 weeks after severe AKI, in association with less-activated macrophages. Macrophage Irf4 deletion also protected against renal fibrosis in unilateral ureteral obstruction. Bone marrow-derived monocytes (BMDMs) from MΦ Irf4-/- mice had diminished chemotactic responses to macrophage chemoattractants, with decreased activation of AKT and PI3 kinase and increased PTEN expression. PI3K and AKT inhibitors markedly decreased chemotaxis in wild-type BMDMs, and in a cultured macrophage cell line. There was significant inhibition of homing of labeled Irf4-/- BMDMs to postischemic kidneys. Renal macrophage infiltration in response to AKI was markedly decreased in MΦ Irf4-/- mice or in wild-type mice with inhibition of AKT activity. Deletion of Irf4 from myeloid cells protected against development of tubulointerstitial fibrosis after severe ischemic renal injury in mice, due primarily to inhibition of AKT-mediated monocyte recruitment to the injured kidney and reduced activation and subsequent polarization into a profibrotic M2 phenotype.

AT2 Receptor Activation Induces Treg Cells and Mitigates Renal Ischemic Injury

Kidney infiltrating immune cells such as monocytes, neutrophils, and T-cells play critical roles in renal ischemia-reperfusion (IR) injury and repair. Recently, angiotensin AT2R has been implicated in protecting kidney against injury and monocytes infiltration, particularly in chronic kidney disease. However, the role of AT2R in IR injury and repair phases, and T-cell modulation is unknown. To address this question, Sprague-Dawley rats were administered with the AT2R agonist C21 (0.3 mg/kg, i.p.) two hour before 30-minute bilateral renal ischemia. IR caused an early (2h post-ischemia) renal functional injury as indicated by elevated proteinuria, blood urea nitrogen and plasma creatinine, and enhanced immune cells (T-cells and CD4 T-cells) infiltration and levels of the proinflammatory cytokines TNF-α and IL-6. The C21 treatment reversed these changes and increased the anti-inflammatory IL-10 level. During the repair phase at day 3 and 5, renal functional injury and T cells infiltration in IR and IR+C21 returned to normal as sham controls. However, high percentages of CD4+FoxP3+ (Tregs, known for their role in repair), and CD4+IL-10+ cells in the kidney were observed in IR+C21 group compared with IR control. These data indicate that the AT2R activation protects the kidney against IR injury and immune cell infiltration in the early phase and modulates CD4 T-cells towards Tregs phenotype, which may have long-term beneficial effects on kidney function.

Inhibition of 12/15 Lipoxygenase (12/15 LOX) Improves Renal Recovery and Function Post Renal Ischemia Reperfusion (IR) injury in Male Spontaneous Hypertensive Rats (SHR)

Acute kidney injury (AKI) due to ischemia reperfusion (IR) is a serious complication in clinical settings and the male gender is often associated with greater severity and mortality following AKI vs. age-matched females. Recent clinical and basic science studies further suggest that renal ischemic injury increases the likelihood of developing hypertension and hypertensive subjects are likely to have greater AKI severity. Despite the widespread prevalence of hypertension and AKI, what mediates renal IR injury leading to increased risk of later developing cardiovascular and renal diseases in either sex is poorly understood. Elevated 12/15-LOX activity has been reported in hypertension and in many kidney diseases. The goal of the current study was to test the hypothesis that enhanced activation of 12/15-LOX in hypertensive males results in greater increases in endoplasmic reticulum (ER) stress and tubular cell death leading to impaired post recovery compared females following renal IR. 13-week old male and female SHR were subjected to sham or 30-minute warm bilateral IR (n=6/group). Blood and urine were collected 24 hrs and 7 days after IR; kidneys were harvested 7 days post-IR for biochemical, histological, and Western blot analysis. IR increased plasma creatinine (Pcr) and blood urea nitrogen (BUN) in both male and female SHR compared to respective sham controls at 24 hrs (PIR =0.0001; Psex*IR=0.2). At 7 days post-IR, Pcr and BUN remained elevated in male SHR but returned to baseline levels in females (Pcr: PIR =0.03; Psex*IR=0.04; BUN: PIR <0.05; Psex*IR=0.05). Histological examination of kidneys 7 days post-IR showed increases in damaged tubules (PIR=0.0003, Psex*IR=0.0019) and tubular cell death (PIR=0.001; Psex*IR=0.001) in males vs. females SHR. Delayed recovery of renal function in male SHR was associated with an upregulation of renal 12/15-LOX protein (PIR<0.05; Psex*IR=0.008), increased lipid peroxidation (PIR=0.008; Psex*IR=0.018), and ER stress protein levels (PIR=0.05; Psex*IR=0.01) compared to sham-controls. To assess the contribution of 12/15 LOX on impaired recovery from IR in male SHR, additional rats were randomized to receive vehicle or the specific 12/15-LOX inhibitor ML355 (30 mg/kg i.p.; n=5/group) 1 hr prior to sham/IR and every other day up to 7 days. Treatment with ML355 1) reduced lipid peroxidation (PIR*TxT =0.02) and ER stress protein levels (PIR*TxT =0.05), 2) prevented IR-induced tubular damage (PIR*TxT=0.02) and tubular cell death (PIR*TxT=0.04), and 3) improved renal function (Pcr: PIR*TxT =0.0067; BUN: PIR*TxT =0.042) compared to vehicle-treated males following IR. In conclusion, our data demonstrate that enhanced activation of 12/15-LOX in the kidney contributes to impaired renal recovery post-IR in male SHR.

RENALASE PROTECTS AGAINST SALT-INDUCED RENAL INJURY BY REGULATING NECROPTOSIS

Objective: Renalase, an enzyme that can metabolize catecholamine, was recently reported to attenuate ischaemic and toxic renal injury. The aim of the study was to investigate the functions and regulation mechanisms of renalase in protection against salt-induced renal injury. Design and method: 1. A total of 515 Chinese participants from 124 families were eligible for this study in 2004. We followed up this cohort in 2009, 2012 and 2018, respectively. 30 tagging SNPs from necroptosis-related genes (RIPK1, RIPK3 and MLKL) were genotyped to investigate the associations with necroptosis and the incidence of subclinical renal damage (SRD). 2. To investigate the role of necroptosis in the development of salt-induced renal injury and the protective effects of renalase on salt-induced renal injury, cultured HK-2 cells, renalase knockout (KO) mice and SS rats were treated with high salt and recombinant renalase exogenously. Necroptosis related to key regulators, apoptosis, inflammation, reactive oxygen species production were analyzed. Results: 1. During 14 years of follow-up, 38 (11.8%) participants developed SRD. RIPK1 SNP rs3736724, MLKL SNPs rs11640974 and rs12924203 were significantly associated with SRD incidence over 14 years. Gene-based analysis found that MLKL was significantly associated with SRD incidence over 14-year follow-up (P = 0.036) after adjustment for multiple testing. 2. High salt significantly increased the proportions of apoptotic and necrotic cells, and the expressions of related necroptosis (RIPK1, RIPK3 and MLKL) in a dose-dependent manner. Besides, high salt increased MDA, NADPH content and suppressed SOD; and increased TNF-alpha, IL-6, and MCP-1 levels. Knockdown of RIPK1, RIPK3 or MLKL with small interfering RNA (siRNA) significantly abrogated the aforementioned effects. Consistent with in vitro findings, high salt diet significantly increased necroptosis in SS rats. Recombinant renalase significantly decreased apoptosis and necroptosis in high salt-treated HK2 cells and SS rats. Similarly, renalase KO mice exacerbated kidney injury in animals subjected to high-salt intake, and administering renalase inhibited necroptosis and reduced salt-induced renal injury. Conclusions: Our results suggest that necroptosis plays an important role in salt-induced renal injury, and renalase protects against renal injury by inhibiting necroptosis.

The Restoration of Vitamin D Levels Slows the Progression of Renal Ischemic Injury in Rats Previously Deficient in Vitamin D.

Chronic kidney disease (CKD) remains a global public health problem. The initial damage after ischemia/reperfusion (I/R) injury plays an important role in the pathogenesis of acute kidney injury (AKI) and predisposition to CKD. Several studies have been showing that nontraditional risk factors such as AKI and hypovitaminosis D could also be involved in CKD progression. Vitamin D deficiency (VDD) is associated with hemodynamic changes, activation of inflammatory pathways and renal disease progression (RDP) following I/R-AKI. Strategies for prevention and/or slowing RDP have been determined and the sufficiency of vitamin D has been emerging as a renoprotective factor in many diseases. Therefore, we investigated the effect of the restoration of vitamin D levels in the progression of I/R injury (IRI) in rats previously deficient in vitamin D. On day 30, male Wistar rats were submitted to bilateral 45 min IRI and divided into three groups: IRI, standard diet for 120 days; VDD+IRI, vitamin D-free diet for 120 days; and VDD+IRI+R, vitamin D-free diet in the first 30 days and just after I/R, we reintroduced the standard diet in the last 90 days. After the 120-day protocol, VDD+IRI+R rats presented an improvement in the renal function and renal protein handling followed by a smaller fractional interstitial area. Furthermore, those animals exhibited a reestablishment regarding the hemodynamic parameters and plasma levels of aldosterone, urea and PTH. In addition, the restoration of vitamin D levels reestablished the amount of MCP1 and the renal expressions of CD68+ and CD3+ cells in the VDD+IRI+R rats. Also, VDD+IRI+R rats showed a restoration regarding the amount of collagen type III and renal expressions of fibronectin, vimentin and α-SMA. Such changes were also accompanied by a reestablishment on the renal expression of VDR, Klotho, JG12, and TGF-β1. Our findings indicate that the restoration of vitamin D levels not only improved the renal function and hemodynamics but also reduced the inflammation and fibrosis lesions observed in I/R-AKI associated with VDD. Thus, monitoring of vitamin D status as well as its replacement in the early stages of kidney injury may be a therapeutic alternative in the mitigation of renal disease progression.

Male Patients may be More Vulnerable to Acute Kidney Injury After Colorectal Surgery in an Enhanced Recovery Program: A Propensity Score Matching Analysis.

Although many reports have shown that enhanced recovery after surgery (ERAS) programs improve the perioperative outcomes of patients undergoing colorectal surgery, the prevalence of early acute kidney injury (AKI) after surgery in such patients requires attention. Protective roles of the female sex in terms of chronic kidney disease and progression of ischemic renal injury have been described in many studies. We thus explored whether a sex difference was evident in terms of postoperative AKI in a colorectal ERAS setting. From January 2017 to August 2019, 453 patients underwent laparoscopic colorectal cancer resection in an enhanced recovery program. Of these, 217 female patients were propensity score (PS)-matched with 236 male patients. Then, 215 patients of either sex were compared in terms of postoperative renal function and complications. Among the PS-matched patients, the incidence of AKI was significantly higher in male than female patients (24.2% vs. 9.8%, P < 0.001). Male patients also exhibited a greater reduction in the postoperative estimated glomerular filtration rate, compared with female patients. The male sex was associated with an approximately threefold increase in the risk of AKI. The rate of surgical complications was significantly higher in male than female patients. Caution must be taken to prevent postoperative AKI in patients (particularly males) participating in colorectal ERAS programs. The mechanism underlying the sex difference remains unclear. Additional studies are required to determine whether male patients require perioperative management that differs from that of females, to prevent postoperative AKI.

English

Cardiac arrest (CA) is a sudden interruption in the effective blood flow due to heart failure. The current research aimed to conduct the pathophysiological and histopathological analysis in the kidney in asphyxial cardiac arrest rat model. Cardiac arrest was induced by intravenous injection of vecuronium bromide (2 mg/kg), following stop of mechanical ventilation. Rats were kept on the CA condition for 5 minutes. After that, cardiopulmonary resuscitation (CPR) was done to achieve return of spontaneous circulation (ROSC) following intravenous injection of epinephrine bolus (0.005 mg/kg), sodium bicarbonate (1 mEq/kg) and turn on mechanical ventilation. Then Rats were sacrificed after cardiopulmonary resuscitation (CPR) following asphyxial CA at 6 hrs, 12 hrs, 1 day, 2 days, and 5 days. The intensity of renal injury measured by the serum levels of blood urea nitrogen (BUN), creatinine (Crtn). Moreover, Hematoxylin &amp; eosin, and Periodic Acid Schiff staining in the kidney was done for evaluating the renal histopathological changes. Furthermore, COX-2 immunoreactivity and western analysis were performed in the kidney. Survival rate declined following ROSC compared to the sham group, it showed 80% at 6 hrs and decreased time-dependently to 8% at 5 days. In this study, serum BUN and Crtn levels and renal histopathological scores significantly increased after ROSC in CA. Moreover, COX-2 expression also increased after ROSC in comparison to the sham group with its peak level at 5 days following CA. Renal histological damage score and COX-2 expression were upregulated after ROSC following CA. These results direct that COX-2 takes part in the asphyxial CA-induced ischemic renal injury

Epigenetic Regulation of the N-Terminal Truncated Isoform of Matrix Metalloproteinase-2 (NTT-MMP-2) and Its Presence in Renal and Cardiac Diseases.

Several clinical and experimental studies have documented a compelling and critical role for the full-length matrix metalloproteinase-2 (FL-MMP-2) in ischemic renal injury, progressive renal fibrosis, and diabetic nephropathy. A novel N-terminal truncated isoform of MMP-2 (NTT-MMP-2) was recently discovered, which is induced by hypoxia and oxidative stress by the activation of a latent promoter located in the first intron of the MMP2 gene. This NTT-MMP-2 isoform is enzymatically active but remains intracellular in or near the mitochondria. In this perspective article, we first present the findings about the discovery of the NTT-MMP-2 isoform, and its functional and structural differences as compared with the FL-MMP-2 isoform. Based on publicly available epigenomics data from the Encyclopedia of DNA Elements (ENCODE) project, we provide insights into the epigenetic regulation of the latent promoter located in the first intron of the MMP2 gene, which support the activation of the NTT-MMP-2 isoform. We then focus on its functional assessment by covering the alterations found in the kidney of transgenic mice expressing the NTT-MMP-2 isoform. Next, we highlight recent findings regarding the presence of the NTT-MMP-2 isoform in renal dysfunction, in kidney and cardiac diseases, including damage observed in aging, acute ischemia-reperfusion injury (IRI), chronic kidney disease, diabetic nephropathy, and human renal transplants with delayed graft function. Finally, we briefly discuss how our insights may guide further experimental and clinical studies that are needed to elucidate the underlying mechanisms and the role of the NTT-MMP-2 isoform in renal dysfunction, which may help to establish it as a potential therapeutic target in kidney diseases.

Activation of hypoxia-sensing pathways promotes renal ischemic preconditioning following myocardial infarction.

Ischemic heart disease is the leading cause of death worldwide and is frequently comorbid with chronic kidney disease. Physiological communication is known to occur between the heart and the kidney. Although primary dysfunction in either organ can induce dysfunction in the other, a clinical entity known as cardiorenal syndrome, mechanistic details are lacking. Here, we used a model of experimental myocardial infarction (MI) to test effects of chronic cardiac ischemia on acute and chronic kidney injury. Surprisingly, chronic cardiac damage protected animals from subsequent acute ischemic renal injury, an effect that was accompanied by evidence of chronic kidney hypoxia. The protection observed post-MI was similar to protection observed in a separate group of healthy animals housed in ambient hypoxic conditions prior to kidney injury, suggesting a common mechanism. There was evidence that chronic cardiac injury activates renal hypoxia-sensing pathways. Increased renal abundance of several glycolytic enzymes following MI suggested that a shift toward glycolysis may confer renal ischemic preconditioning. In contrast, effects on chronic renal injury followed a different pattern, with post-MI animals displaying worsened chronic renal injury and fibrosis. These data show that although chronic cardiac injury following MI protected against acute kidney injury via activation of hypoxia-sensing pathways, it worsened chronic kidney injury. The results further our understanding of cardiorenal signaling mechanisms and have implications for the treatment of heart failure patients with associated renal disease.NEW & NOTEWORTHY Experimental myocardial infarction (MI) protects from subsequent ischemic acute kidney injury but worsens chronic kidney injury. Observed protection from ischemic acute kidney injury after MI was accompanied by chronic kidney hypoxia and increased renal abundance of hypoxia-inducible transcripts. These data support the idea that MI confers protection from renal ischemic injury via chronic renal hypoxia and activation of downstream hypoxia-inducible signaling pathways.

Normotensive and hypertensive Immunoglobulin a nephropathy with ischemic renal injury: clinicopathological characteristics and prognosis

Objectives This study aimed to investigate the clinicopathological characteristics and prognosis of normotensive and hypertensive IgAN patients with ischemic renal injury. Methods A total of 344 cases of IgAN with ischemic renal injury were included in the study, including 99 normotensive IgAN patients (28.8%) and 245 hypertensive IgAN patients (71.2%). In addition, 467 IgAN patients without ischemic renal injury were included as controls, including 205 normotensive patients and 262 hypertensive patients. Clinicopathological and prognostic data were collected and analyzed. Results Compared with patients without ischemic renal injury, IgAN patients with ischemic renal injury displayed a higher proportion of hypertention, a higher proportion of ischemic glomerulosclerosis, tubular atrophy/interstitial fibrosis and vascular lesions (all p < .05). There was no significant difference in cumulative survival between the normotensive IgAN patients groups (Log-rank χ2 = 0.479; p = .489). Furthermore, ischemic renal injury was not a risk factor for end-point events in normotensive IgAN patients (HR = 1.103; 95% CI: 0.279–4.365; p = .889). There was lower cumulative survival in hypertensive IgAN patients with ischemic renal injury (Log-rank χ2 = 11.352, p = .001). Moreover, ischemic renal injury was a risk factor for end-point events in hypertensive IgAN patients (HR = 1.889; 95% CI: 1.124–3.178; p = .016). Conclusions Ischemic renal injury can occur in normotensive IgAN patients. Although the pathological changes may not affect the long-term prognosis of normotensive IgAN patients, the prognosis for hypertensive IgAN patients remains poor. Therefore, increased attention should be paid to the clinical management of ischemic lesions in hypertensive IgAN patients.

Targeting Ferroptosis: Pathological Mechanism and Treatment of Ischemia-Reperfusion Injury.

Ischemia-reperfusion (I/R) is a pathological process that occurs in many organs and diseases. Reperfusion, recovery of blood flow, and reoxygenation often lead to reperfusion injury. Drug therapy and early reperfusion therapy can reduce tissue injury and cell necrosis caused by ischemia, leading to irreversible I/R injury. Ferroptosis was clearly defined in 2012 as a newly discovered iron-dependent, peroxide-driven, nonapoptotic form of regulated cell death. Ferroptosis is considered the cause of reperfusion injury. This discovery provides new avenues for the recognition and treatment of diseases. Ferroptosis is a key factor that leads to I/R injury and organ failure. Given the important role of ferroptosis in I/R injury, there is considerable interest in the potential role of ferroptosis as a targeted treatment for a wide range of I/R injury-related diseases. Recently, substantial progress has been made in applying ferroptosis to I/R injury in various organs and diseases. The development of ferroptosis regulators is expected to provide new opportunities for the treatment of I/R injury. Herein, we analytically review the pathological mechanism and targeted treatment of ferroptosis in I/R and related diseases from the perspectives of myocardial I/R injury, cerebral I/R injury, and ischemic renal injury.

Evolving Medical Imaging Techniques for the Assessment of Delayed Graft Function: A Narrative Review.

Purpose of review:Delayed graft function (DGF) is a significant complication that contributes to poorer graft function and shortened graft survival. In this review, we sought to evaluate the current and emerging role of medical imaging modalities in the assessment of DGF and how it may guide clinical management.Sources of information:PubMed, Google Scholar, and ClinicalTrial.gov up until February 2021.Methods:This narrative review first examined the pathophysiology of DGF and current clinical management. We then summarized relevant studies that utilized medical imaging to assess posttransplant renal complications, namely, DGF. We focused our attention on noninvasive, evolving imaging modalities with the greatest potential for clinical translation, including contrast-enhanced ultrasound (CEUS) and multiparametric magnetic resonance imaging (MRI).Key findings:A kidney biopsy in the setting of DGF can be used to assess the degree of ischemic renal injury and to rule out acute rejection. Biopsies are accompanied by complications and may be limited by sampling bias. Early studies on CEUS and MRI have shown their potential to distinguish between the 2 most common causes of DGF (acute tubular necrosis and acute rejection), but they have generally included only small numbers of patients and have not kept pace with more recent technical advances of these imaging modalities. There remains unharnessed potential with CEUS and MRI, and more robust clinical studies are needed to better evaluate their role in the current era.Limitations:The adaptation of emerging approaches for imaging DGF will depend on additional clinical trials to study the feasibility and diagnostic test characteristics of a given modality. This is limited by access to devices, technical competence, and the need for interdisciplinary collaborations to ensure that such studies are well designed to appropriately inform clinical decision-making.