Kidney Tubular Injury Research Articles

Associations of urinary epidermal growth factor and monocyte chemotactic protein-1 with kidney involvement in patients with diabetic kidney disease.

In diabetic kidney disease (DKD), it is important to find biomarkers for predicting initiation and progression of the disease. Besides glomerular damage, kidney tubular injury and inflammation are also involved in the development of DKD. The current study investigated the associations of urinary epidermal growth factor (uEGF), monocyte chemotactic protein-1 (MCP-1) and the uEGF:MCP-1 ratio with kidney involvement in patients at early and advanced stages of DKD. The concentration of uEGF and uMCP-1 was measured in two Chinese population-based studies. The associations of uEGF, uMCP-1 and uEGF/MCP-1 with occurrence of DKD were studied in a cross-sectional study (n = 1811) of early stage DKD. Associations of baseline uEGF, uMCP-1 and uEGF/MCP-1 with kidney outcome were assessed in a longitudinal cohort (n = 208) of advanced-stage DKD. In both studies, positive correlations were found between uEGF/urine creatinine (Cr) and estimated glomerular filtration rate (eGFR) at sampling and between uMCP-1/Cr and urinary albumin:creatinine ratio (uACR). In the cross-sectional study, uEGF/Cr and uEGF/MCP-1 were negatively associated with the occurrence of DKD {odds ratio (OR) 0.65 [95% confidence interval (CI) 0.54-0.79], P < 0.001; 0.82 (0.71-0.94), P = 0.005, respectively}. In the longitudinal cohort, the uEGF:MCP-1 ratio correlated more closely with the percentage change of eGFR slope (r = 0.33, P < 0.001) as compared with uEGF/Cr or uMCP-1/Cr alone. The composite endpoint was defined as end-stage renal disease or 30% reduction of eGFR. These three markers were independently associated with composite endpoint after adjusting for potential confounders [hazard ratio 0.76 (0.59-1.00), P = 0.047 for uEGF/Cr; 1.18 (1.02-1.38), P = 0.028 for uMCP-1/Cr; 0.79 (0.68-0.91), P = 0.001 for uEGF/MCP-1]. In Chinese patients, urinary EGF/MCP-1 was negatively associated with the occurrence of DKD. Moreover, uEGF/MCP-1 had a better ability to predict the composite endpoint and correlated more closely with kidney function decline in advanced DKD as compared with uEGF/Cr or uMCP-1/Cr alone.

Heat Exposure, Volume Status, and Kidney Tubular Injury in Washington Crop Workers

Heat Exposure, Volume Status, and Kidney Tubular Injury in Washington Crop Workers

RIPK3 promotes sepsis-induced acute kidney injury via mitochondrial dysfunction.

Sepsis causes acute kidney injury (AKI) in critically ill patients, although the pathophysiology remains unclear. The receptor-interacting protein kinase-3 (RIPK3), a cardinal regulator of necroptosis, has recently been implicated in the pathogenesis of human disease. In mice subjected to polymicrobial sepsis, we demonstrate that RIPK3 promotes sepsis-induced AKI. Utilizing genetic deletion and biochemical approaches in vitro and in vivo, we identify a potentially novel pathway by which RIPK3 aggravates kidney tubular injury independently of the classical mixed lineage kinase domain-like protein-dependent (MLKL-dependent) necroptosis pathway. In kidney tubular epithelial cells, we show that RIPK3 promotes oxidative stress and mitochondrial dysfunction involving upregulation of NADPH oxidase-4 (NOX4) and inhibition of mitochondrial complex I and -III, and that RIPK3 and NOX4 are critical for kidney tubular injury in vivo. Furthermore, we demonstrate that RIPK3 is required for increased mitochondrial translocation of NOX4 in response to proinflammatory stimuli, by a mechanism involving protein-protein interactions. Finally, we observed elevated urinary and plasma RIPK3 levels in human patients with sepsis-induced AKI, representing potential markers of this condition. In conclusion, we identify a pathway by which RIPK3 promotes kidney tubular injury via mitochondrial dysfunction, independently of MLKL, which may represent a promising therapeutic target in sepsis-induced AKI.

N-acetylcysteine decreases urinary level of neutrophil gelatinase-associated lipocalin in deceased-donor renal transplant recipients: a randomized clinical trial

Context: Acute kidney injury (AKI) is a common complication after kidney transplantation (KT), especially in recipients from deceased donors. Urinary neutrophil gelatinase-associated lipocalin (u-NGAL) is an early and sensitive marker of AKI after transplantation.Objectives: We assessed the renoprotective effect of N-acetylcysteine (NAC) on u-NGAL levels as an early prognostic marker of graft function immediately after transplantation.Materials and methods: A double-blind, randomized, placebo-controlled trial was conducted on 70 deceased-donor KT recipients (www.irct.ir, trial registration number: IRCT2014090214693N4). Patients received 600 mg oral NAC or placebo twice daily from day 0 to 5 and urine samples were taken before, and on the first and fifth days after transplantation. U-NGAL and early graft function were compared between the two groups.Results: NAC significantly reduced u-NGAL levels compared to placebo (p value = 0.02), while improvement in early graft function with NAC did not reach statistical significance.Conclusions: This study showed that NAC administration in deceased-donor KT recipients can reduce tubular kidney injury, evidenced by u-NGAL measurements. Improvement in early graft function needs a larger sample size to reach a statistical conclusion.

Crepidiastrum denticulatum Extract Ameliorates Kidney Ischemia-Reperfusion Injury in Mice

BackgroundCrepidiastrum denticulatum (CD) is a well-known, traditionally consumed vegetable in Korea, which was recently reported to contain bioactive compounds with detoxification and antioxidant properties. Ischemia-reperfusion injury (IRI) is a major problem after renal transplantation. Furthermore, inflammatory responses to IRI exacerbate the resultant renal injury. In the present study, we investigated whether CD extract exhibits renoprotective effects against IR-induced acute kidney injury in mice. Materials and methodsRenal IRI was induced in male C57BL/6 mice by bilateral renal pedicle occlusion for 30 minutes followed by reperfusion for 48 hours. CD extract (75 mg/kg) was administered orally 5 days before IRI. ResultsTreatment with CD extract significantly decreased blood urea nitrogen and serum creatinine levels as well as kidney tubular injury. CD also prevented IRI-induced renal glutathione depletion and increased malondialdehyde levels. Western blotting and reverse transcriptase polymerase chain reaction indicated that CD extract significantly attenuates inducible nitric oxide synthase and toll-like receptor 2/4 protein levels 48 h after IRI. The expression of tumor necrosis factor-α and interleukin-1β was significantly decreased in the CD extract treatment group. ConclusionCD extract improved acute renal IRI through its antioxidant and anti-inflammatory effects. These findings suggest that CD extract is a potential therapeutic agent for acute ischemia-induced renal damage.

Hyperuricemia Induces Wnt5a/Ror2 Gene Expression, Epithelial-Mesenchymal Transition, and Kidney Tubular Injury in Mice.

Hyperuricemia contributes to kidney injury, characterized by tubular injury with epithelial-mesenchymal transition (EMT). Wnt5a/Ror2 signaling drives EMT in many kidney pathologies. This study sought to evaluate the involvement of Wnt5a/Ror2 in hyperuricemia-induced EMT in kidney tubular injury. A hyperuricemia model was performed in male Swiss background mice (3 months old, 30-40 g) with daily intraperitoneal injections of 125 mg/kg body weight (BW) of uric acid. The mice were terminated on day 7 (UA7, n=5) and on day 14 (UA14, n=5). Allopurinol groups (UAl7 and UAl14, each n=5) were added with oral 50 mg/kg BW of allopurinol treatment. The serum uric acid level was quantified, and tubular injury was assessed based on PAS staining. Reverse transcriptase-PCR was done to quantify Wnt5a, Ror2, E-cadherin, and vimentin expressions. IHC staining was done for E-cadherin and collagen I. We used the Shapiro-Wilk for normality testing and one-way ANOVA for variance analysis with a P<0.05 as significance level using SPSS 22 software. The hyperuricemia groups had a higher uric acid level, which was associated with a higher tubular injury score. Meanwhile, the allopurinol groups had a significantly lower uric acid level and tubular injury than the uric acid groups. Reverse transcriptase-PCR revealed downregulation of the E-cadherin expression. While vimentin and collagen I expression are upregulated, which was associated with a higher Wnt5a expression. However, the allopurinol groups had reverse results. Immunostaining revealed a reduction in E-cadherin staining in the epithelial cells and collagen I positive staining in the epithelial cells and the interstitial areas. Hyperuricemia induced tubular injury, which might have been mediated by EMT through the activation of Wnt5a.

FGF21 is induced in cisplatin nephrotoxicity to protect against kidney tubular cell injury.

Cisplatin, a widely used cancer therapy drug, induces nephrotoxicity or acute kidney injury (AKI), but the underlying mechanism remains unclear, and renal protective approaches are not available. Fibroblast growth factor (FGF)21 is an endocrine factor that regulates glucose uptake, metabolism, and energy expenditure. However, recent work has also implicated FGF21 in cellular stress response under pathogenic conditions. The role and regulation of FGF21 in AKI are unclear. Here, we show that FGF21 was dramatically induced during cisplatin treatment of renal tubular cells in vitro and mouse kidneys in vivo. The inductive response was suppressed by pifithrin (a pharmacological inhibitor of P53), suggesting a role of P53 in FGF21 induction. In cultured renal tubular cells, knockdown of FGF21 aggravated cisplatin-induced apoptosis, whereas supplementation of recombinant FGF21 was protective. Consistently, recombinant FGF21 alleviated cisplatin-induced kidney dysfunction, tissue damage, and tubular apoptosis in mice. Mechanistically, FGF21 suppressed P53 induction and activation during cisplatin treatment. Together, these results indicate that FGF21 is induced during cisplatin nephrotoxicity to protect renal tubules, and recombinant FGF21 may have therapeutic potential.-Li, F., Liu, Z., Tang, C., Cai, J., Dong, Z. FGF21 is induced in cisplatin nephrotoxicity to protect against kidney tubular cell injury.

Worsening Renal Function in Patients With Acute Heart Failure Undergoing Aggressive Diuresis Is Not Associated With Tubular Injury.

Worsening renal function (WRF) in the setting of aggressive diuresis for acute heart failure treatment may reflect renal tubular injury or simply indicate a hemodynamic or functional change in glomerular filtration. Well-validated tubular injury biomarkers, N-acetyl-β-d-glucosaminidase, neutrophil gelatinase-associated lipocalin, and kidney injury molecule 1, are now available that can quantify the degree of renal tubular injury. The ROSE-AHF trial (Renal Optimization Strategies Evaluation-Acute Heart Failure) provides an experimental platform for the study of mechanisms of WRF during aggressive diuresis for acute heart failure because the ROSE-AHF protocol dictated high-dose loop diuretic therapy in all patients. We sought to determine whether tubular injury biomarkers are associated with WRF in the setting of aggressive diuresis and its association with prognosis. Patients in the multicenter ROSE-AHF trial with baseline and 72-hour urine tubular injury biomarkers were analyzed (n=283). WRF was defined as a ≥20% decrease in glomerular filtration rate estimated with cystatin C. Consistent with protocol-driven aggressive dosing of loop diuretics, participants received a median 560 mg IV furosemide equivalents (interquartile range, 300-815 mg), which induced a urine output of 8425 mL (interquartile range, 6341-10 528 mL) over the 72-hour intervention period. Levels of N-acetyl-β-d-glucosaminidase and kidney injury molecule 1 did not change with aggressive diuresis (both P>0.59), whereas levels of neutrophil gelatinase-associated lipocalin decreased slightly (-8.7 ng/mg; interquartile range, -169 to 35 ng/mg; P<0.001). WRF occurred in 21.2% of the population and was not associated with an increase in any marker of renal tubular injury: neutrophil gelatinase-associated lipocalin (P=0.21), N-acetyl-β-d-glucosaminidase (P=0.46), or kidney injury molecule 1 (P=0.22). Increases in neutrophil gelatinase-associated lipocalin, N-acetyl-β-d-glucosaminidase, and kidney injury molecule 1 were paradoxically associated with improved survival (adjusted hazard ratio, 0.80 per 10 percentile increase; 95% confidence interval, 0.69-0.91; P=0.001). Kidney tubular injury does not appear to have an association with WRF in the context of aggressive diuresis of patients with acute heart failure. These findings reinforce the notion that the small to moderate deteriorations in renal function commonly encountered with aggressive diuresis are dissimilar from traditional causes of acute kidney injury.

The effects of furosemide on kidney damage in acute kidney injury rat models

The most frequent cause of acute kidney injury (AKI) is ischemia reperfusion injuries that causes inflammation. Furosemide is still used in AKI’s therapy. The advantages and disadvantages of furosemide in AKI remain controversial. The aim of the study was to investigate the effect of furosemide on kidney damage in AKI rat models. Twenty-five male (2-3 months old) Sprague-Dawley rats were divided into 5 groups; sham operation (SO, n=5), ischemic-reperfusion (IR, n=5), IR+furosemide 3.6 mg/kgBW (IR+F1, n=5), IR+furosemide 7.2 mg/kgBW (IR+F2, n=5), and IR+furosemide 14.4 mg/kgBW (IR+F3, n=5). Abdominal surgery was performed under ketamine anesthesia to produce ischemic reperfusion (IR) by mean of renal artery clamping for 45 min. Urine output, serum creatinine level, tubular injury score, and TLR4 gene expression were examined to investigate kidney damage. Periodic acid-schiff (PAS) staining was measured to examine kidney tubular injury. Data were analyzed using One-Way ANOVA and Kruskal- Wallis test with significance level of p 0.05) creatinine clearance compared to IR (0.009±0.003) while administration of 14.4 mg/kgBW furosemide (0.009±0.004) denoted equal creatinine clearance to IR (p>0,05). Kidney tubular injury score of 3.6 mg/kgBW furosemide (2.89±0.13) was lower (p>0.05) than IR (3.26±0.19) whereas 7.2 mg/kgBW and 14.4 mg/kgBW furosemide (3.55±0.26; 3.83±0.19) were higher (p 0.05) and 14.4 mg/ kgBW furosemide (1.63±0.12) was significantly higher (p<0.05) than IR. In conclusion, administration of 3.6 mg/kgBW furosemide reduces kidney damage in AKI rat models while higher dosages (7.2 mg/kgBW and 14.4 mg/kgBW) increase kidney damage.

Febuxostat attenuates ER stress mediated kidney injury in a rat model of hyperuricemic nephropathy.

Hyperuricemia contributes to kidney tubular injury and kidney fibrosis. However, the underlying mechanism remains unclear. Here we examined the role of RTN1A, a novel endoplasmic reticulum (ER)-associated protein and ER stress in hyperuricemic nephropathy. We first found the expression of RTN1A and ER stress markers was significantly increased in kidney biopsies of hyperuricemia patients with kidney injury. In a rat model of hyperuricemic nephropathy (HN) established by oral administration of a mixture of adenine and potassium oxonate, increased expression of RTN1A and ER stress was shown in tubular and interstitial compartment of rat kidneys. Treatment of Febuxostat, a new selective inhibitor of xanthine oxidase (XO), not only attenuated renal tubular injury and tubulointerstitial fibrosis, but also reduced uric acid crystals deposition in HN rat kidneys. In vitro, Febuxostat also reduced ER stress and apoptosis in uric acid treated tubular epithelial cells. Our data suggest that RTN1A and ER stress mediate tubular cell injury and kidney fibrosis in HN. Urate-lowering therapy (ULT) with Febuxostat attenuates uric-acid induced ER stress in renal tubular cells and the progression of HN.

Biomarkers of tubulointerstitial damage and function in type 1 diabetes

ObjectiveTo evaluate biomarkers of renal tubulointerstitial damage and function in type 1 diabetes with and without diabetic kidney disease.Research design and methodsCross-sectional case-control study of Diabetes Control and Complications Trial/Epidemiology...

Clinical utility of single molecule counting technology for quantification of KIM-1 in patients with heart failure and chronic kidney disease

BackgroundAcute kidney injury (AKI) is associated with high morbidity and mortality, and may lead to chronic kidney disease (CKD). Traditional serum biomarkers for acute and chronic renal dysfunction are insensitive and nonspecific. While urinary kidney injury molecule-1 (KIM-1) is a sensitive and specific measure of kidney tubular injury, it is difficult to obtain in acute settings. Thus, our objective was to develop a highly sensitive immunoassay for plasma KIM-1. MethodsA novel plasma KIM-1 immunoassay was developed using Single Molecule Counting technology (SMC). It was clinically validated in: 120 healthy subjects to establish a preliminary reference range; 25 healthy subjects to assess biological variability; 200 patients with heart failure (CHF); and 60 patients from a CKD case control. ResultsSMC KIM-1 assay provided a limit of detection of 1.4pg/mL (reporting range from 2pg/mL to 1000pg/mL). Inter-assay precision was 9–15% CV. Median KIM-1 value in healthy subjects was 119pg/mL with a RR 95th percentile of 292pg/mL. KIM-1 demonstrated low weekly biological variability over 6weeks. KIM-1 was elevated in patients with CKD or CHF. Adjusted odds ratios for differentiating CHF or CKD from controls were 9.6 (95% CI 2.7–35.0) and 3.6 (95% CI 1.1–11.6), respectively. In CHF, KIM-1 values correlated inversely with eGFR (Spearman R=−0.32, p<0.0001). ConclusionsPlasma KIM-1 is quantifiable in healthy volunteers, elevated in CKD and CHF patients, and correlates with eGFR. Additional investigation is needed to determine if KIM-1 provides prognostic value for CKD and CHF patient outcomes.

Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone Protects Against Acute Kidney Injury-Mediated Chronic Kidney Disease: Role of Oxidative Stress.

Acute kidney injury induced by ischemia/reperfusion (IR) is a frequent complication in hospitalized patients. Mineralocorticoid receptor antagonism has shown to be helpful against renal IR consequences; however, the potential benefit of novel nonsteroidal mineralocorticoid receptor antagonists such as finerenone has to be further explored. In this study, we evaluated the efficacy of finerenone to prevent the acute and chronic consequences of ischemic acute kidney injury. For the acute study (24 hours), 18 rats were divided into sham, bilateral renal ischemia of 25 minutes, and rats that received 3 doses of finerenone at 48, 24, and 1 hour before the ischemia. For the chronic study (4 months), 23 rats were divided into sham, rats that underwent 45 minutes of bilateral ischemia, and rats treated with finerenone at days 2 and 1 and 1 hour before IR. We found that after 24 hours of reperfusion, the untreated IR rats presented kidney dysfunction and tubular injury. Kidney injury molecule-1 and neutrophil gelatinase associated to lipolacin mRNA levels were increased. In contrast, the rats treated with finerenone displayed normal kidney function and significantly lesser tubular injury and kidney injury molecule-1 and neutrophil gelatinase associated to lipolacin levels. After 4 months, the IR rats developed chronic kidney disease, evidenced by kidney dysfunction, increased proteinuria and renal vascular resistance, tubular dilation, extensive tubule-interstitial fibrosis, and an increase in kidney transforming growth factor-β and collagen-I mRNA. The transition from acute kidney injury to chronic kidney disease was fully prevented by finerenone. Altogether, our data show that in the rat, finerenone is able to prevent acute kidney injury induced by IR and the chronic and progressive deterioration of kidney function and structure.

Wnt4 is a novel biomarker for the early detection of kidney tubular injury after ischemia/reperfusion injury.

Earlier intervention after acute kidney injury would promote better outcomes. Our previous study found that Wnt proteins are promptly upregulated after ischemic kidney injury. Thus, we assessed whether Wnt4 could be an early and sensitive biomarker of tubular injury. We subjected mice to bilateral ischemia/reperfusion injury (IRI). Kidney and urinary Wnt4 expression showed an early increase at 3 hours and increased further at 24 hours post-IRI and was closely correlated with histopathological alterations. Serum creatinine slightly increased at 6 hours, indicating that it was less sensitive than Wnt4 expression. These data were further confirmed by clinical study. Both kidney and urinary Wnt4 expression were significantly increased in patients diagnosed with biopsy-proven minimal change disease (MCD) with tubular injury, all of whom nevertheless had normal estimated glomerular filtration rate (eGFR) and serum creatinine. The increased Wnt4 expression also strongly correlated with histopathological alterations in these MCD patients. In conclusion, this is the first demonstration that increases in both kidney and urinary Wnt4 expression can be detected more sensitively and earlier than serum creatinine after kidney injury. In particular, urinary Wnt4 could be a potential noninvasive biomarker for the early detection of tubular injury.

Abstract 055: Benefit of Mineralocorticoid Receptor Antagonism in Acute Kidney Injury: Role of Smooth Muscle Rac1

Introduction: Renal ischemia/reperfusion (IR) is a major cause of acute kidney injury (AKI). The benefit of novel non-steroidal MR antagonists such as finerenone in the IR context has not been evaluated and the mechanisms underlying the benefit of MR antagonism remain unclear. Objectives: To test the efficacy of finerenone in ischemic AKI and to evaluate the specific contribution of the MR expressed in endothelial or smooth muscle cell (SMC) in renal IR injury. Methods: We included 18 male C57/B6 mice that were divided in: sham, renal ischemia for 20 min and IR plus treatment with finerenone (10 mg/kg) by gavage once a day at -48, -24 and -1 h before IR. Alternatively, MR inactivation in endothelial cells (MR endoKO mice /Vecadh-cre) or in smooth muscle cells (MR SMCKO mice/SMA-cre) was induced in 3-month-old mice. Sham surgery or bilateral renal IR for 20 min was performed and mice were studied 24 h after reperfusion. Primary rat SMC cultures were used to assess the signaling pathways modulated by MR. Results: In C57/B6 WT, MR fl/fl and MR endoKO mice, IR induced kidney dysfunction and tubular injury. After IR, Finerenone-treated mice and the MR SMCKO mice presented normal renal function and a significant reduction of histological alterations, while MR endoKO mice were not protected. The benefit of finerenone and MR KO in SMC was associated with reduced oxidative stress-mediated lipid peroxidation as compared to MR fl/fl or WT mice. In aldosterone-stimulated rat SMC, we observed a 100% increase in hydrogen peroxide production and a 2-fold increase in Rac1 activity; MR and Rac1 antagonism blunted these effects. Moreover, mice deficient of Rac1 in SMC were also protected against ischemic AKI. Conclusion: Finerenone limits renal injury induced by IR. Moreover, genetic deletion of MR in SMC only has similar effects. This benefit was associated with reduced oxidative stress, by affecting oxidative stress production via SMC Rac1.

24 Urine concentrations of nephrin, podocalyxin, NGAL, and KIM-1 could serve as biomarkers to evaluate kidney function in pregnancy and postpartum kidney injury recovery in preeclampsia

Introduction Glomerular podocyte and podocyte glycoprotein shedding have emerged as a significant kidney lesion in preeclampsia (PE). Objective To determine if podocyte glycoprotein nephrin and podocalyxin, and tubular injury biomarkers neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) could serve as biomarkers to evaluate kidney injury and postpartum kidney functional recovery in PE. Methods Urine specimen was collected from 88 pregnant women (28 normal pregnancy, 15 complicated with chronic hypertension (CHT), 11 mild PE, and 34 severe PE). Among the study subjects, urine specimens were also obtained from 11 normal and 9 severe PE pregnancies 6–8 weeks after delivery. Urine concentrations of nephrin, podocalyxin, soluble vascular cell adhesion molecule 1 (sVCAM-1), NGAL, KIM-1, and creatinine were measured by enzyme-linked immunosorbent assay (ELISA). Creatinine concentration was used to normalize urine levels of testing biomarkers for each sample. ANOVA and paired t -test were used for statistical analysis. Pearson product-moment correlation coefficient (Pearson r) was used to analyze the correlation of urine biomarkers with the urine proteinuria-to-creatinine ratio in severe PE. A p value of Results (1) Urine levels of nephrin, podocalyxin, sVCAM-1, NGAL, and KIM-1 were significantly higher in severe PE than in normal pregnant women before delivery, p p p Conclusions Nephrin and podocalyxin are podocyte glycoproteins. Increased nephrin and/or podocalyxin shedding are indicators of podocyte injury. sVCAM could be released from dysfunctioned glomerular endothelial cells or leaked from maternal plasma through the glomerular basement barrier. NGAL and KIM-1 are considered biomarkers of both acute or chronic kidney tubular injury. Thus, our results suggest that not only podocyte injury, but also tubular dysfunction occur in severe PE. Reduced shedding of these biomarkers in severe PE after delivery is an indicator of kidney function recovery in PE. Therefore, our data suggest that these urine biomarkers could serve as biomarkers to assess kidney injury during pregnancy and to evaluate postpartum kidney functional recovery in PE and pregnancy-associated kidney disorders.

Novel Omega-3 Fatty Acid Epoxygenase Metabolite Reduces Kidney Fibrosis.

Cytochrome P450 (CYP) monooxygenases epoxidize the omega-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid into novel epoxydocosapentaenoic acids (EDPs) that have multiple biological actions. The present study determined the ability of the most abundant EDP regioisomer, 19,20-EDP to reduce kidney injury in an experimental unilateral ureteral obstruction (UUO) renal fibrosis mouse model. Mice with UUO developed kidney tubular injury and interstitial fibrosis. UUO mice had elevated kidney hydroxyproline content and five-times greater collagen positive fibrotic area than sham control mice. 19,20-EDP treatment to UUO mice for 10 days reduced renal fibrosis with a 40%–50% reduction in collagen positive area and hydroxyproline content. There was a six-fold increase in kidney α-smooth muscle actin (α-SMA) positive area in UUO mice compared to sham control mice, and 19,20-EDP treatment to UUO mice decreased α-SMA immunopositive area by 60%. UUO mice demonstrated renal epithelial-to-mesenchymal transition (EMT) with reduced expression of the epithelial marker E-cadherin and elevated expression of multiple mesenchymal markers (FSP-1, α-SMA, and desmin). Interestingly, 19,20-EDP treatment reduced renal EMT in UUO by decreasing mesenchymal and increasing epithelial marker expression. Overall, we demonstrate that a novel omega-3 fatty acid metabolite 19,20-EDP, prevents UUO-induced renal fibrosis in mice by reducing renal EMT.

Urinary Neutrophil Gelatinase-Associated Lipocalin (NGAL) in Patients with Obstructive Sleep Apnea.

BackgroundObstructive sleep apnea (OSA) is a well-established risk factor for hypertension and cardiovascular morbidity and mortality. More recently, OSA has been implicated as an independent risk factor for chronic kidney disease. Urinary neutrophil gelatinase-associated lipocalin (NGAL) is a well-accepted early biomarker of subclinical kidney tubular injury, preceding an increase in serum creatinine. The goal of this study was to determine if an association exists between OSA and increased urinary NGAL levels.MethodsWe prospectively enrolled adult patients from the sleep clinic of an academic medical center. Each underwent polysomnography and submitted a urine specimen upon enrollment. We measured NGAL and creatinine levels on all urine samples before participants received treatment with continuous positive airway pressure (CPAP), and, in a subset of OSA patients, after CPAP therapy. We compared the urinary NGAL/creatinine ratio between untreated participants with and without OSA, and within a subset of 11 OSA patients also after CPAP therapy.ResultsA total of 49 subjects were enrolled: 16 controls based on an apnea-hypopnea index (events with at least 4% oxygen desaturation; AHI-4%) <5 events/hour (mean AHI-4% = 0.59 +/- 0.60); 33 OSA patients based on an AHI-4% >5 events/hour (mean AHI-4% = 43.3 +/- 28.1). OSA patients had a higher mean body-mass index than the control group (36.58 +/- 11.02 kg/m2 vs. 26.81 +/- 6.55 kg/m2, respectively; p = 0.0005) and were more likely to be treated for hypertension (54.5% vs. 6.25% of group members, respectively; p = 0.0014). The groups were otherwise similar in demographics, and there was no difference in the number of diabetic subjects or in the mean serum creatinine concentration (control = 0.86 +/- 0.15 mg/dl, OSA = 0.87 +/- 0.19 mg/dl; p = 0.7956). We found no difference between the urinary NGAL-to-creatinine ratios among untreated OSA patients versus control subjects (median NGAL/creatinine = 6.34 ng/mg vs. 6.41 ng/mg, respectively; p = 0.4148). Furthermore, CPAP therapy did not affect the urinary NGAL-to-creatinine ratio (p = 0.7758 for two-tailed, paired t-test).ConclusionsIn this prospective case-control study comparing patients with severe, hypoxic OSA to control subjects, all with normal serum creatinine, we found no difference between urinary levels of NGAL. Furthermore, CPAP therapy did not change these levels pre- and post-treatment.

Protective Effect of Polydeoxyribonucleotide Against Renal Ischemia-Reperfusion Injury in Mice

BackgroundPolydeoxyribonucleotide (PDRN) is an A2A receptor agonist that induces vascular endothelial growth factor (VEGF) production during the pathological condition of low tissue perfusion. Ischemia-reperfusion injury (IRI) is a major problem after renal transplantation. In the present study, we investigated whether PDRN exhibits reno-protective effects against ischemia-reperfusion–induced acute kidney injury in mice. MethodsRenal ischemia-reperfusion injury was induced in male C57BL/6 mice by bilateral renal pedicle occlusion for 30 minutes, followed by reperfusion for 48 hours. PDRN (8 mg/kg body weight intraperitoneally) was administered 30 minutes before IRI. ResultsTreatment with PDRN significantly decreased neutrophil gelatinase-associated lipocalin levels in the urine, blood urea nitrogen level, and serum creatinine levels as well as kidney tubular injury. Western blotting showed that PDRN significantly increased the levels of vascular endothelial growth factor and B-cell lymphoma protein and attenuated p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, inducible nitric oxide synthase, and Bcl-2–associated X protein levels 48 hours after IRI. ConclusionsOur findings suggest that PDRN is a potential therapeutic agent for acute ischemia-induced renal damage.

NF-κB transcriptional inhibition ameliorates cisplatin-induced acute kidney injury (AKI).

The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) cell signaling pathway is important in inflammation and cell survival. Inflammation and cell death in the kidney are features of cisplatin-induced AKI. While it is known that cisplatin induces NF-κB signaling in the kidney, the NF-κB responsive genes and the effect of direct NF-κB transcriptional inhibition in cisplatin-induced AKI is not known. Mice injected with cisplatin, 25mg/kg, developed AKI, acute tubular necrosis (ATN) and apoptosis on day 3. Mice were treated with JSH-23 (20 or 40 mg/kg) which directly affects NF-κB transcriptional activity. Kidney function, tubular injury (ATN, serum neutrophil gelatinase-associated lipocalin [NGAL], but not apoptosis) and myeloperoxidase (MPO) activity were significantly improved by JSH-23 (40 mg/kg). Sixty one NF-κB responsive genes were increased by cisplatin of which 21 genes were decreased by JSH-23. Genes that were decreased by JSH-23 that are known to play a role in cisplatin-induced AKI were IL-10, IFN-γ, chemokine [C-C motif] ligand 2 (CCL2) and caspase-1. Another gene, caspase recruitment domain family, member 11 (CARD11), not previously known to play a role in AKI, was increased more than 20-fold and completely inhibited by JSH-23. CXCL1 and TNF-α, known mediators of cisplatin-induced AKI, were decreased by JSH-23. RIPK1 and 3, receptor-interacting serine/threonine-protein kinases, that play an important role in necroptosis, were decreased by JSH-23. In mouse proximal tubule cells in culture, JSH-23 resulted in an increase in apoptosis suggesting that the mechanism of protection against AKI by JSH-23 is not due to a direct effect on proximal tubules. In conclusion, NF-κB transcriptional inhibition in cisplatin-induced AKI ameliorates kidney function and ATN without a significant effect on apoptosis and is associated with a decrease pro-inflammatory mediators and CARD11.