Effects of Mineralocorticoid Receptor Blockade and Statins on Kidney Injury Marker 1 (KIM-1) in Female Rats Receiving L-NAME and Angiotensin II.

Kidney injury molecule-1 (KIM-1) is a biomarker of renal injury and a predictor of cardiovascular disease. Aldosterone, via activation of the mineralocorticoid receptor, is linked to cardiac and renal injury. However, the impact of mineralocorticoid receptor activation and blockade on KIM-1 is uncertain. We investigated whether renal KIM-1 is increased in a cardiorenal injury model induced by L-NAME/ANG II, and whether mineralocorticoid receptor blockade prevents the increase in KIM-1. Since statin use is associated with lower aldosterone, we also investigated whether administering eiSther a lipophilic statin (simvastatin) or a hydrophilic statin (pravastatin) prevents the increase in renal KIM-1. Female Wistar rats (8-10 week old), consuming a high salt diet (1.6% Na+), were randomized to the following conditions for 14 days: control; L-NAME (0.2 mg/mL in drinking water)/ANG II (225 ug/kg/day on days 12-14); L-NAME/ANG II + eplerenone (100 mg/kg/day p.o.); L-NAME/ANG II + pravastatin (20 mg/kg/day p.o.); L-NAME/ANG II + simvastatin (20 mg/kg/day p.o.). Groups treated with L-NAME/ANG II had significantly higher blood pressure, plasma and urine aldosterone, cardiac injury/stroke composite score, and renal KIM-1 than the control group. Both eplerenone and simvastatin reduced 24-h urinary KIM-1 (p = 0.0046, p = 0.031, respectively) and renal KIM-1 immunostaining (p = 0.004, p = 0.037, respectively). Eplerenone also reduced renal KIM-1 mRNA expression (p = 0.012) and cardiac injury/stroke composite score (p = 0.04). Pravastatin did not affect these damage markers. The 24-h urinary KIM-1, renal KIM-1 immunostaining, and renal KIM-1 mRNA expression correlated with cardiac injury/stroke composite score (p < 0.0001, Spearman ranked correlation = 0.69, 0.66, 0.59, respectively). In conclusion, L-NAME/ANG II increases renal KIM-1 and both eplerenone and simvastatin blunt this increase in renal KIM-1.

Urinary levels of kidney injury molecule-1 (KIM-1) and interleukin-18 (IL-18) in children and adolescents with hyperuricemia.

PURPOSE: Hyperuricemia may lead to silent tissue damage and increase the risk of some diseases, including kidney diseases. Increased serum uric acid concentration induces inflammatory pathways and promotes kidney damage. This study aimed to determine whether hyperuricemia influences the levels of urinary kidney injury markers in children and adolescents with hyperuricemia, assessed by the urinary concentrations of interleukin-18, a biomarker of inflammation, and kidney injury molecule-1 (KIM-1), a biomarker of kidney injury. MATERIAL AND METHODS: The study included 73 children and adolescents (32 males and 41 females) aged 2-18 years. They were divided into two groups: hyperuricemia (HU) group (n â€‹= â€‹48) and normouricemia - reference group (R) (n â€‹= â€‹25). The concentrations of urinary interleukin-18 and KIM-1 were measured using an ELISA kit and were normalized for urinary creatinine (cr.) concentration. RESULTS: The median interleukin-18/cr. Levels in the HU group were significantly higher than in the R group (median, Q1-Q3) 21.83 (11.32-35.96) and 12.68 (7.11-24.04), respectively, (p â€‹< â€‹0.05). The KIM-1/cr. in the HU group and the R group were (median, Q1-Q3) 0.79 (0.45-1.03) and 0.81 (0.59-1.01), respectively, and the difference was not significant. KIM-1/cr. did not differ between the groups. Interleukin-18/cr. ratio correlated positively with serum uric acid concentration (r â€‹= â€‹0.24, p â€‹< â€‹0.05). CONCLUSIONS: Interleukin-18/cr., but not KIM-1/cr. was higher in children with hyperuricemia. Hyperuricemia results in increased IL-18 in urine, in absence of other markers of kidney injury, suggesting inflammation in the kidney. Additional studies on the adults should be done, to confirm this hypothesis.

miR-142 Targets TIM-1 in Human Endothelial Cells: Potential Implications for Stroke, COVID-19, Zika, Ebola, Dengue, and Other Viral Infections.

T-cell immunoglobulin and mucin domain 1 (TIM-1) has been recently identified as one of the factors involved in the internalization of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in human cells, in addition to angiotensin-converting enzyme 2 (ACE2), transmembrane serine protease 2 (TMPRSS2), neuropilin-1, and others. We hypothesized that specific microRNAs could target TIM-1, with potential implications for the management of patients suffering from coronavirus disease 2019 (COVID-19). By combining bioinformatic analyses and functional assays, we identified miR-142 as a specific regulator of TIM-1 transcription. Since TIM-1 has been implicated in the regulation of endothelial function at the level of the blood-brain barrier (BBB) and its levels have been shown to be associated with stroke and cerebral ischemia-reperfusion injury, we validated miR-142 as a functional modulator of TIM-1 in human brain microvascular endothelial cells (hBMECs). Taken together, our results indicate that miR-142 targets TIM-1, representing a novel strategy against cerebrovascular disorders, as well as systemic complications of SARS-CoV-2 and other viral infections.

Two independent modes of kidney stone suppression achieved by AIM/CD5L and KIM-1.

The prevalence of kidney stones is increasing and its recurrence rate within the first 5 years is over 50%. No treatments that prevent the occurrence/recurrence of stones have reached the clinic. Here, we show that AIM (also called CD5L) suppresses stone development and improves stone-associated physical damages. The N-terminal domain of AIM associates with calcium oxalate crystals via charge-based interaction to impede the development of stones, whereas the 2nd and C-terminal domains capture the inflammatory DAMPs to promote their phagocytic removal. Accordingly, when stones were induced by glyoxylate in mice, recombinant AIM (rAIM) injection dramatically reduced stone development. Expression of injury molecules and inflammatory cytokines in the kidney and overall renal dysfunction were abrogated by rAIM. Among various negatively charged substances, rAIM was most effective in stone prevention due to its high binding affinity to crystals. Furthermore, only AIM was effective in improving the physical complaints including bodyweight-loss through its DAMPs removal effect. We also found that tubular KIM-1 may remove developed stones. Our results could be the basis for the development of a comprehensive therapy against kidney stone disease.

Altered expression of Tim family molecules and an imbalanced ratio of Tim-3 to Tim-1 expression in patients with type 1 diabetes.

Background: T-cell immunoglobulin and mucin domain (Tim) proteins are immunomodulatory molecules that play key roles in the regulation of T-cell activation. Published studies have reported that Tim molecules are involved in the pathogenesis of certain autoimmune diseases. Type 1 diabetes (T1D) is an autoimmune disease in which T cells mediate the destruction of islet ß cells. However, the expression of Tim molecules in T1D remains unclear. In this study, we measured the expression of Tim family molecules as well as T-cell subset-specific transcription factors in T1D patients, and we explored the possible involvement of Tim molecules in the pathogenesis of T1D. Methods: Ninety T1D patients, Thirty-six type 2 diabetes (T2D) patients and forty healthy controls (HCs) were recruited for this study. Peripheral blood mononuclear cells (PBMCs) were isolated, RNA was extracted from the PBMCs and reverse transcribed into cDNA, and gene expression patterns were analysed by RT-qPCR. The expression of Tim molecules in different T-cell subsets was analysed by flow cytometry. Results: Compared with that in HCs, the mRNA expression of Tim-1 and RORC was increased in T1D patients (P=0.0355 and P=0.0423, respectively), while the expression of Tim-3 was decreased (P=0.0013). In addition, compared with HCs, the ratio of Tim-3 to Tim-1 expression in diabetic patients was decreased (P<0.0001 for T1D and P=0.0387 for T2D). The ratios of T-Bet to GATA3 expression and RORC to FOXP3 expression were higher in T1D patients than in HCs (P=0.0042 and P=0.0066, respectively). Furthermore, the T1D patients with defective islet function had more significant imbalances in the Tim-3/Tim-1 and RORC/FOXP3 ratios (P<0.0001, and P=0.001, respectively). Moreover, Both Tim-3 expression in CD4+ T cells and the Tim-3 to Tim-1 ratio were elevated in T1D in the remission phase compared to T1D. Conclusion: Our study revealed altered expression of Tim molecules in T1D patients. The imbalanced ratios of Tim-3/Tim-1 expression were more pronounced in T1D patients with defective islet function. However, alterations in Tim molecule expression are mitigated in T1D in the remission phase. All these findings suggest that Tim family molecules may be involved in the pathogenesis of T1D.

In-silico analysis of interacting pathways through KIM-1 protein interaction in diabetic nephropathy.

BACKGROUND: Human Kidney Injury Molecule-1, also known as HAVCR-1 (Hepatitis A virus cellular receptor 1), belongs to the cell-surface protein of immunoglobulin superfamily involved in the phagocytosis by acting as scavenger receptor epithelial cells. The study focused on pinpointing the mechanisms and genes that interact with KIM-1. METHODS: This in-silico study was done from March 2019 to December 2019. The Enrichment and protein-protein interaction (PPI) network carefully choose proteins. In addition, the diagramed gene data sets were accomplished using FunRich version 3.1.3. It was done to unveil the proteins that may affect the regulation of HAVCR1 or may be regulated by this protein. These genes were then further considered in pathway analysis to discover the dysregulated pathways in diabetic nephropathy. The long list of differentially expressed genes is meaningless without pathway analysis. RESULTS: Critical pathways that are dysregulated in diabetic nephropathy patients have been identified. These include Immune System (Total = 237, P < 0.05), Innate Immune System (Total = 140, P < 0.05), Cytokine Signaling Immune system (Total = 116, P < 0.05), Adaptive Immune System (Total = 85) and Neutrophil degranulation (Total = 78). CONCLUSION: The top 5 genes that are interacting directly with HIVCR1 include CASP3, CCL2, SPP1, B2M, and TIMP1 with degrees 161, 144, 108, 107, and 105 respectively for Immune system pathways (Innate Immune System, Cytokine Signaling Immune system, Adaptive Immune System and Neutrophil degranulation).

Review of potential biomarkers of inflammation and kidney injury in diabetic kidney disease.

Diabetic kidney disease is expected to increase rapidly over the coming decades with rising prevalence of diabetes worldwide. Current measures of kidney function based on albuminuria and estimated glomerular filtration rate do not accurately stratify and predict individuals at risk of declining kidney function in diabetes. As a result, recent attention has turned towards identifying and assessing the utility of biomarkers in diabetic kidney disease. This review explores the current literature on biomarkers of inflammation and kidney injury focussing on studies of single or multiple biomarkers between January 2014 and February 2020. Multiple serum and urine biomarkers of inflammation and kidney injury have demonstrated significant association with the development and progression of diabetic kidney disease. Of the inflammatory biomarkers, tumour necrosis factor receptor-1 and -2 were frequently studied and appear to hold most promise as markers of diabetic kidney disease. With regards to kidney injury biomarkers, studies have largely targeted markers of tubular injury of which kidney injury molecule-1, beta-2-microglobulin and neutrophil gelatinase-associated lipocalin emerged as potential candidates. Finally, the use of a small panel of selective biomarkers appears to perform just as well as a panel of multiple biomarkers for predicting kidney function decline.

Tim-1 mucin domain-mutant mice display exacerbated atherosclerosis.

BACKGROUND AND AIMS: Increasing evidence has shown that immune checkpoint molecules of the T-cell immunoglobulin and mucin domain (Tim) family are associated with diverse physiologic and pathologic processes. Previous studies of the role of Tim-1 in atherosclerosis using anti-Tim-1 antibodies have yielded contradictory results. We thus aimed to investigate atherosclerosis development in Tim-1 deficient mice. METHODS: Mice with a specific loss of the Tim-1 mucin-domain (Tim-1Δmucin) and C57BL/6 (WT) mice received a single injection of a recombinant adeno-associated virus encoding murine Pcsk9 (rAAV2/8-D377Y-mPcsk9) and were fed a Western type diet for 13 weeks to introduce atherosclerosis. RESULTS: Tim-1Δmucin mice developed significantly larger lesions in the aortic root compared to WT mice, with significantly more macrophages and a trend towards a larger necrotic core. Furthermore, Tim-1Δmucin mice showed a significant loss of IL-10+ B cells and regulatory B cell subsets and increased pro-atherogenic splenic follicular B cells compared to WT mice. Moreover, Tim-1Δmucin mice displayed a dramatic reduction in Th2-associated immune response compared to controls but we did not observe any changes in humoral immunity. CONCLUSIONS: In summary, Tim-1Δmucin mice displayed a profound impairment in IL-10+ B cells and an imbalance in the Th1/Th2 ratio, which associated with exacerbated atherosclerosis.

TIM-1 promotes proliferation and metastasis, and inhibits apoptosis, in cervical cancer through the PI3K/AKT/p53 pathway.

BACKGROUND: T-cell immunoglobulin mucin-1 (TIM-1) has been reported to be associated with the biological behavior of several malignant tumors; however, it is not clear whether it has a role in cervical cancer (CC). METHODS: TIM-1 expression in cervical epithelial tumor tissues and cells was detected by immunohistochemistry or real-time quantitative-PCR and western blotting. CC cells from cell lines expressing low levels of TIM-1 were infected with lentiviral vectors encoding TIM-1. Changes in the malignant behavior of CC cells were assessed by CCK-8, wound healing, Transwell migration and invasion assays, and flow cytometry in vitro; while a xenograft tumor model was established to analyze the effects of TIM-1 on tumor growth in vivo. Changes in the levels of proteins related to the cell cycle, apoptosis, and Epithelial-mesenchymal transition (EMT) were determined by western blotting. RESULTS: TIM-1 expression was higher in CC tissues, than in high grade squamous intraepithelial lesion, low grade squamous intraepithelial lesion, or normal cervical tissues, and was also expressed in three CC cell lines. In HeLa and SiHa cells overexpressing TIM-1, proliferation, invasion, and migration increased, while whereas apoptosis was inhibited. Furthermore, TIM-1 downregulated the expression of p53, BAX, and E-cadherin, and increased cyclin D1, Bcl-2, Snail1, N-cadherin, vimentin, MMP-2, and VEGF. PI3K, p-AKT, and mTOR protein levels also increased, while total AKT protein levels remained unchanged. CONCLUSIONS: Our study indicated that TIM-1 overexpression promoted cell migration and invasion, and inhibited cell apoptosis in CC through modulation of the PI3K/AKT/p53 and PI3K/AKT/mTOR signaling pathways, and may be a candidate diagnostic biomarker of this disease.

Altered kidney function induced by SARS-CoV-2 infection and acute kidney damage markers predict survival outcomes of COVID-19 patients: a prospective pilot study.

BACKGROUND: Literature with regard to coronavirus disease 2019 (COVID-19) associated morbidities and the risk factors for death are still emerging. In this study, we investigated the presence of kidney damage markers and their predictive value for survival among hospitalized subjects with COVID-19. METHODS: Forty-seven participants was included and grouped as: 'COVID-19 patients before treatment', 'COVID-19 patients after treatment', 'COVID-19 patients under treatment in intensive care unit (ICU)', and 'controls'. Kidney function tests and several kidney injury biomarkers were compared between the groups. Cumulative rates of death from COVID-19 were determined using the Kaplan-Meier method. The associations between covariates including kidney injury markers and death from COVID-19 were examined, as well. RESULTS: Serum creatinine and cystatin C levels, urine Kidney Injury Molecule-1 (KIM-1)/creatinine ratio, and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), CKD-EPI cystatin C, and CKD-EPI creatinine-cystatin C levels demonstrated significant difference among the groups. The most significant difference was noted between the groups 'COVID-19 patients before treatment' and 'COVID-19 patients under treatment in ICU'. Advancing age, proteinuria, elevated serum cystatin C, and urine KIM-1/creatinine ratio were all significant univariate correlates of death (p < 0.05, for all). However, only elevated urine KIM-1/creatinine ratio retained significance in an age, sex, and comorbidities adjusted multivariable Cox regression (OR 6.11; 95% CI: 1.22-30.53; p = 0.02), whereas serum cystatin C showing only a statistically non-significant trend (OR 1.42; 95% CI: 0.00-2.52; p = 0.09). CONCLUSIONS: Our findings clearly demonstrated the acute kidney injury related to COVID-19. Moreover, urine KIM-1/creatinine ratio was associated with COVID-19 specific death.

High dietary salt intake increases urinary NGAL excretion and creatinine clearance in healthy young adults.

In rodents and older patients with elevated blood pressure (BP), high dietary sodium increases excretion of biomarkers of kidney injury, but it is unclear whether this effect occurs in healthy young adults. The purpose of this study was to determine whether short-term high dietary salt increases urinary excretion of the kidney injury biomarkers neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) in healthy young adults. Twenty participants participated in a double-blind, placebo-controlled, randomized crossover study. For 10 days each, participants were asked to consume salt (3,900 mg sodium) or placebo capsules. We measured BP during each visit, obtained 24-h urine samples for measurements of electrolytes, NGAL, and KIM-1, and assessed creatinine clearance. Compared with placebo, salt loading increased daily urinary sodium excretion (placebo: 130.3 ± 62.4 mmol/24 h vs. salt: 287.2 ± 72.0 mmol/24 h, P < 0.01). There was no difference in mean arterial BP (placebo: 77 ± 7 mmHg vs. salt: 77 ± 6 mmHg, P = 0.83) between conditions. However, salt loading increased the urinary NGAL excretion rate (placebo: 59.8 ± 44.4 ng/min vs. salt: 80.8 ± 49.5 ng/min, P < 0.01) and increased creatinine clearance (placebo: 110.5 ± 32.9 mL/min vs. salt: 145.0 ± 24.9 mL/min, P < 0.01). Urinary KIM-1 excretion was not different between conditions. In conclusion, in healthy young adults 10 days of dietary salt loading increased creatinine clearance and increased urinary excretion of the kidney injury biomarker marker NGAL but not KIM-1.NEW & NOTEWORTHY In healthy young adults, 10 days of dietary salt loading increased creatinine clearance and increased urinary excretion of the kidney injury biomarker marker neutrophil gelatinase-associated lipocalin despite no change in resting blood pressure.

(-)-α-Bisabolol as a protective agent against epithelial renal cytotoxicity induced by amphotericin B.

INTRODUCTION: Amphotericin B (AmB), used for systemic fungal infections, has a limited clinical application because of its high nephrotoxicity. Natural antioxidant and anti-inflammatory substances have been widely studied for protection against drug-induced nephrotoxicity. α-Bisabolol (BIS) has demonstrated a nephroprotective effect on both in vitro and in vivo models. AIMS: The aim of this work was to evaluate the effect of BIS against AmB-induced nephrotoxicity in vitro. MATERIAL AND METHODS: LLC-MK2 cells were pre- and post-treated with non-toxic BIS concentrations and/or AmB IC50 (13.97 µM). Cell viability was assessed by MTT [(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)] assay. Flow cytometry analyses were used to assess cell death mechanism, production of reactive oxidative stress (ROS) and mitochondrial transmembrane potential. Kidney Injury Molecule-1 (KIM-1) levels were measured via ELISA. KEY FINDINGS: The present work showed that BIS pretreatment (125; 62.5 and 31.25 µM) increased cell viability when compared to the group treated only with AmB IC50. AmB treatment induced both necrosis (7-AAD-labeled cells) and late apoptosis (AnxV-labeled). BIS was able to prevent the occurrence of these events. These effects were associated with a decrease of ROS accumulation, improving transmembrane mitochondrial potential and protecting against tubular cell damage, highlighted by the inhibition of KIM-1 release after BIS treatment. SIGNIFICANCE: BIS presented a potential effect on model of renal cytotoxicity induced by AmB, bringing perspectives for the research of new nephroprotective agents.

NLRP3 inflammasome in rosmarinic acid-afforded attenuation of acute kidney injury in mice.

Cisplatin (CP) is a well-known anticancer drug used to effectively treat various kinds of solid tumors. CP causes acute kidney injury (AKI) and unfortunately, there is no therapeutic approach in hand to prevent AKI. Several signaling pathways are responsible for inducing AKI which leads to inflammation in proximal convoluted tubule cells in the kidney. Furthermore, the nucleotide-binding oligomerization domain (NOD)-like receptor containing pyrin domain 3 (NLRP3) inflammasome is involved in the CP-induced AKI. In this study, we investigated therapeutic effects of rosmarinic acid (RA) against inflammation-induced AKI. RA was orally administered at the dose of 100 mg/kg for two consecutive days after 24 h of a single injection of CP at the dose of 20 mg/kg administered intraperitoneally in Swiss albino male mice. Treatment of RA inhibited the activation of NLRP3 signaling pathway by blocking the activated caspase-1 and downstream signal molecules such as IL-1ß and IL18. CP activated HMGB1-TLR4/MyD88 axis was also found to be downregulated with the RA treatment. Activation of nuclear factor-κB and elevated protein expression of cyclooxygenase-2 (COX-2) were also found to be downregulated in RA-treated animals. Alteration of early tubular injury biomarker, kidney injury molecule-1 (KIM-1), was found to be subsided in RA-treated mice. RA has been earlier reported for antioxidant and anti-inflammatory properties. Our findings show that blocking a critical step of inflammasome signaling pathway by RA treatment can be a novel and beneficial approach to prevent the CP-induced AKI.

Juzentaihoto improves adenine-induced chronic renal failure in BALB/c mice via suppression of renal fibrosis and inflammation.

Renal inflammation and fibrosis are observed in underlying diseases associated with the pathological progression of chronic kidney disease (CKD). The inhibition of renal inflammation and fibrosis is one method to suppress the progression of CKD. Juzentaihoto (TJ-48), a Kampo medicine, effectively relieves chronic wasting diseases and fatigue and has been reported to decrease inflammation. In this study, we investigated whether TJ-48 has a renal protective effect and its underlying mechanism in mice with adenine-induced CKD. BALB/c mice were divided into four groups for examination: (1) control, (2) dietary restriction, (3) adenine, and (4) adenine + TJ-48. Biochemical and histological analyses, gene expression analysis, and complete blood counts were performed. TJ-48 treatment decreased tubular damage and fibrosis. TJ-48 also decreased creatinine levels exacerbated by adenine, suppressed the mRNA expression of tumor necrosis factor-α, chemokine ligand 2, transforming growth factor-ß, and kidney injury molecule-1, and decreased the neutrophil/lymphocyte ratio increased by adenine. TJ-48 exerts a renoprotective effect possibly via the suppression of fibrosis and inflammation.

Effect of a 3% gelatin solution on urinary KIM-1 levels in patients after thyroidectomy: a preliminary randomized controlled trial.

Optimal fluid therapy significantly affects the maintenance of proper tissue perfusion and, consequently, kidney function. An adverse effect of colloids on kidney function is related to the incidence of postoperative kidney failure. The study aimed to assess the effect of a 3% gelatin solution on kidney function based on the urinary kidney injury molecule-1 (uKIM-1) level. This study used a parallel design and enrolled 64 adult patients with a mean age of 52.5 ± 13.1 years, all of whom underwent a thyroidectomy procedure under general anesthesia. Patients were randomly assigned to three comparison groups, each receiving a different dose of 3% gelatin solution during the thyroidectomy procedure. The patients from study groups A (n = 21) and B (n = 21) received a 3% gelatin solution at a dose of 30 ml/kg and 15 ml/kg body weight, respectively, during the first hour of the procedure. The patients from the control group C (n = 22) received an isotonic multi-electrolyte solution. Serum creatinine levels were determined, and urine samples were collected to determine levels of uKIM-1 before, 2 h, and 24 h after surgery. The patients' demographic data, type and volume of fluid and hemodynamic status during the surgery were collected from relevant anesthesia protocols and were included in the study data. There were no statistically significant changes between groups in hemodynamic parameters such as systolic and diastolic blood pressure, heart rate, and oxygen saturation values. A statistically significant increase in uKIM-1 level was noted in patients receiving the 3% gelatin solution regardless of the dose. A statistically significant difference in uKIM-1 level was observed between groups A, B, and C measured 24 h after surgery, with the highest uKIM-1 level in group A. Measurement of uKIM-1 level could be an early and sensitive biomarker of kidney injury. Kidney toxicity of a 3% gelatin solution, evaluated based on the level of uKIM-1 in urine, correlates with transfused fluid volume. This study was retrospectively registered in the ISRCTN clinical trials registry (ISRCTN73266049, 08/04/2021: https://www.isrctn.com/ISRCTN73266049 ).

LncRNA-ATB participates in the regulation of calcium oxalate crystal-induced renal injury by sponging the miR-200 family.

BACKGROUND: LncRNA-ATB is a long noncoding RNA (lncRNA) activated by transforming growth factor ß (TGF-ß) and it has important biological functions in tumours and nontumour diseases. Meanwhile, TGF-ß is the most critical regulatory factor in the process of nephrotic fibrosis and calcium oxalate (CaOx) crystal-induced renal injury. The present study aimed to investigate the biological function and mechanism of lncRNA-ATB in CaOx crystal-induced renal injury. METHODS: The expression level of lncRNA-ATB was detected by quantitative reverse-transcription polymerase chain reaction (qRT-PCR), the expression levels of epithelial-mesenchymal transition (EMT) markers, TGF-ß1 and Kidney Injury Molecule-1 (KIM-1) were detected by qRT-PCR, immunofluorescence staining or western blot analysis, cell proliferation was measured with a CCK-8 kit, cell apoptosis was measured by flow cytometry and TUNEL staining, and cell injury was detected with the Cytotoxicity lactate dehydrogenase (LDH) Assay kit and the expression level of KIM-1. RESULTS: The expression levels of lncRNA-ATB and TGF-ß1 were significantly increased in HK-2 cells after coincubation with calcium oxalate monohydrate (COM). COM stimulation caused significant injury in the HK-2 cells, induced cell apoptosis, inhibited cell proliferation, and induced EMT changes. After COM stimulation, the expression levels of the epithelial cell markers E-cadherin and zonula occludens (ZO)-1 in HK-2 cells significantly decreased, whereas the levels of the mesenchymal cell markers N-cadherin, vimentin and α-smooth muscle actin (α-SMA) significantly increased. Interference with lncRNA-ATB expression significantly relieved the COM-induced cell injury, cell apoptosis, proliferation inhibition, and EMT changes. The expression levels of the microRNA-200 (miR-200) family in the HK-2 cells after coincubation with COM were significantly decreased. MiR-200a mimics relieved the COM-induced cell injury, apoptosis, proliferation inhibition, and EMT changes, whereas miR-200a inhibitors abolished the lncRNA-ATB interference-induced relief of the COM-induced cell injury, apoptosis, proliferation inhibition, and EMT. CONCLUSION: LncRNA-ATB promoted the COM-induced cell injury, cell apoptosis, proliferation inhibition, and EMT to participate in the process of CaOx crystal-induced renal injury by sponging miR-200s.

Nicorandil Decreases Renal Injury in Patients With Coronary Heart Disease Complicated With Type I Cardiorenal Syndrome.

ABSTRACT: Cardiorenal syndrome (CRS) is a group of disorders in which heart or kidney dysfunction worsens each other. This study aimed to explore the improvement effect of nicorandil on cardiorenal injury in patients with type I CRS. Patients with coronary heart disease complicated with type I CRS were enrolled. Based on the conventional treatment, the patients were prospectively randomized into a conventional treatment group and a nicorandil group, which was treated with 24 mg/d nicorandil intravenously for 1 week. Fasting peripheral venous blood serum and urine were collected before and at the end of treatment. An automatic biochemical analyzer and enzyme linked immunosorbent assay were used to detect B-type brain natriuretic peptide (BNP), serum creatinine (Scr) and cystatin C (Cys-C), renal injury index-kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and interleukin-18 (IL-18) levels. The left ventricular ejection fraction was measured by echocardiography. All measurements were not significantly different between the nicorandil and conventional treatment groups before treatment (all P > 0.05), and BNP, Scr, Cys-C, NGAL, KIM-1, and IL-18 were decreased in the 2 groups at the end of treatment (all P < 0.05). Compared with the conventional treatment group, BNP, Scr, Cys-C, NGAL, KIM-1, and IL-18 were more significantly decreased in the nicorandil group (all P < 0.05) and left ventricular ejection fraction was more significantly increased (P < 0.05). Therefore, nicorandil could significantly improve the cardiac and renal function of patients with type I CRS. This may prove to be a new therapeutic tool for improving the prognosis and rehabilitation of type I CRS.

Effect of Dipeptidyl Peptidase-4 (DPP-4) Inhibition on Biomarkers of Kidney Injury and Vascular Calcification in Diabetic Kidney Disease: A Randomized Controlled Trial.

INTRODUCTION: Dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycemic control and have pleiotropic effects on kidney injury, albuminuria, and vascular inflammation, especially in animal models. We evaluated the effects of a potent DPP4 inhibitor (gemigliptin) on these processes among patients with diabetic kidney disease (DKD). METHODS: This study employed a multicenter, prospective, randomized, placebo-controlled design. A total of 201 participants were enrolled and randomly assigned to one of two groups, one received treatment with 50 mg gemigliptin daily along with standard care for diabetes mellitus for 6 months. The changes in the coronary calcium score (CAC score), cardio-ankle vascular index (CAVI), estimated glomerular filtration rate (eGFR), vascular calcification level, and tubular renal injury marker expression were evaluated at baseline and 6 months. RESULTS: In total, 182 patients completed the study. Significant reductions in hemoglobin A1C levels were observed in both groups. The changes in the CAC score, CAVI, eGFR, and level of proteinuria over the 6 months of the study did not significantly differ between the gemigliptin and control groups. However, biomarkers of vascular calcification, including serum bone alkaline phosphatase and kidney injury, including urine neutrophil gelatinase-associated lipocalin (NGAL)/Cr and urine liver fatty acid-binding protein (L-FABP)/Cr, were improved significantly in the gemigliptin treatment group compared with the control group. No serious adverse events were observed during the study. CONCLUSION: Our study showed that gemigliptin significantly improved the expression of renal tubular injury biomarkers and vascular calcification levels among patients with DKD; however, gemigliptin did not affect renal function or coronary calcification compared with those observed in the control. A larger study with a longer follow-up is essential to verify these beneficial effects. Clinical Trials. This trial is registered with ClinicalTrials.Gov Identifier NCT04705506.

Autophagy gene ATG7 regulates albumin transcytosis in renal tubule epithelial cells.

Receptor-mediated albumin transport in proximal tubule epithelial cells (PTECs) is important to control proteinuria. Autophagy is an evolutionarily conserved degradation pathway, and its role in intracellular trafficking through interactions with the endocytic pathway has recently been highlighted. Here, we determined whether autophagy regulates albumin transcytosis in PTECs and suppresses albumin-induced cytotoxicity using human proximal tubule (HK-2) cells. The neonatal Fc receptor (FcRn), a receptor for albumin transcytosis, is partially colocalized with autophagosomes. Recycling of FcRn was attenuated, and FcRn accumulated in autophagy-related 7 (ATG7) knockdown HK-2 cells. Colocalization of FcRn with RAB7-positive late endosomes and RAB11-positive recycling endosomes was reduced in ATG7 knockdown cells, which decreased recycling of FcRn to the plasma membrane. In ATG7 or autophagy-related 5 (ATG5) knockdown cells and Atg5 or Atg7 knockout mouse embryonic fibroblasts, albumin transcytosis was significantly reduced and intracellular albumin accumulation was increased. Finally, the release of kidney injury molecule-1, a marker of tubule injury, from ATG7 or ATG5 knockdown cells was increased in response to excess albumin. In conclusion, suppression of autophagy in tubules impairs FcRn transport, thereby inhibiting albumin transcytosis. The resulting accumulation of albumin induces cytotoxicity in tubules.NEW & NOTEWORTHY Albumin transport in proximal tubule epithelial cells (PTECs) is important to control proteinuria. The neonatal Fc receptor (FcRn), a receptor for albumin transcytosis, is partially colocalized with autophagosomes. Recycling of FcRn to the plasma membrane was decreased in autophagy-related 7 (ATG7) knockdown cells. In addition, albumin transcytosis was decreased in ATG7 or autophagy-related 5 (ATG5) knockdown PTECs. Finally, release of kidney injury molecule-1 from ATG7 or ATG5 knockdown cells was increased in response to excess albumin.