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1.
Cell Death Dis ; 15(6): 401, 2024 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-38849370

RESUMEN

The triggering receptor expressed on myeloid cells 2 (TREM2) is an immune receptor that affects cellular phenotypes by modulating phagocytosis and metabolism, promoting cell survival, and counteracting inflammation. Its role in renal injury, in particular, unilateral ureteral obstruction (UUO) or ischemia-reperfusion injury (IRI)-induced renal injury remains unclear. In our study, WT and Trem2-/- mice were employed to evaluate the role of TREM2 in renal macrophage infiltration and tissue injury after UUO. Bone marrow-derived macrophages (BMDM) from both mouse genotypes were cultured and polarized for in vitro experiments. Next, the effects of TREM2 on renal injury and macrophage polarization in IRI mice were also explored. We found that TREM2 expression was upregulated in the obstructed kidneys. TREM2 deficiency exacerbated renal inflammation and fibrosis 3 and 7 days after UUO, in association with reduced macrophage infiltration. Trem2-/- BMDM exhibited increased apoptosis and poorer survival compared with WT BMDM. Meanwhile, TREM2 deficiency augmented M1 and M2 polarization after UUO. Consistent with the in vivo observations, TREM2 deficiency led to increased polarization of BMDM towards the M1 proinflammatory phenotype. Mechanistically, TREM2 deficiency promoted M1 and M2 polarization via the JAK-STAT pathway in the presence of TGF-ß1, thereby affecting cell survival by regulating mTOR signaling. Furthermore, cyclocreatine supplementation alleviated cell death caused by TREM2 deficiency. Additionally, we found that TREM2 deficiency promoted renal injury, fibrosis, and macrophage polarization in IRI mice. The current data suggest that TREM2 deficiency aggravates renal injury by promoting macrophage apoptosis and polarization via the JAK-STAT pathway. These findings have implications for the role of TREM2 in the regulation of renal injury that justify further evaluation.


Asunto(s)
Apoptosis , Macrófagos , Glicoproteínas de Membrana , Ratones Endogámicos C57BL , Receptores Inmunológicos , Factores de Transcripción STAT , Transducción de Señal , Animales , Macrófagos/metabolismo , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/deficiencia , Receptores Inmunológicos/genética , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/deficiencia , Glicoproteínas de Membrana/genética , Ratones , Factores de Transcripción STAT/metabolismo , Quinasas Janus/metabolismo , Riñón/patología , Riñón/metabolismo , Ratones Noqueados , Masculino , Fibrosis , Daño por Reperfusión/patología , Daño por Reperfusión/metabolismo , Daño por Reperfusión/genética , Obstrucción Ureteral/patología , Obstrucción Ureteral/metabolismo , Obstrucción Ureteral/complicaciones , Polaridad Celular , Serina-Treonina Quinasas TOR/metabolismo , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Lesión Renal Aguda/genética
2.
Front Immunol ; 15: 1365226, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38812511

RESUMEN

Objective: The aberrant mobilization and activation of various T lymphocyte subpopulations play a pivotal role in the pathogenesis of diabetic kidney disease (DKD), yet the regulatory mechanisms underlying these processes remain poorly understood. Our study is premised on the hypothesis that the dysregulation of immune checkpoint molecules on T lymphocytes disrupts kidney homeostasis, instigates pathological inflammation, and promotes DKD progression. Methods: A total of 360 adult patients with DKD were recruited for this study. The expression of immune checkpoint molecules on T lymphocytes was assessed by flow cytometry for peripheral blood and immunofluorescence staining for kidney tissue. Single-cell sequencing (scRNA-seq) data from the kidneys of DKD mouse model were analyzed. Results: Patients with DKD exhibited a reduction in the proportion of CD3+TIM-3+ T cells in circulation concurrent with the emergence of significant albuminuria and hematuria (p=0.008 and 0.02, respectively). Conversely, the incidence of infection during DKD progression correlated with an elevation of peripheral CD3+TIM-3+ T cells (p=0.01). Both univariate and multivariate logistic regression analysis revealed a significant inverse relationship between the proportion of peripheral CD3+TIM-3+ T cells and severe interstitial mononuclear infiltration (OR: 0.193, 95%CI: 0.040,0.926, p=0.04). Immunofluorescence assays demonstrated an increase of CD3+, TIM-3+ and CD3+TIM-3+ interstitial mononuclear cells in the kidneys of DKD patients as compared to patients diagnosed with minimal change disease (p=0.03, 0.02 and 0.002, respectively). ScRNA-seq analysis revealed decreased gene expression of TIM3 on T lymphocytes in DKD compared to control. And one of TIM-3's main ligands, Galectin-9 on immune cells showed a decreasing trend in gene expression as kidney damage worsened. Conclusion: Our study underscores the potential protective role of TIM-3 on T lymphocytes in attenuating the progression of DKD and suggests that monitoring circulating CD3+TIM3+ T cells may serve as a viable strategy for identifying DKD patients at heightened risk of disease progression.


Asunto(s)
Nefropatías Diabéticas , Receptor 2 Celular del Virus de la Hepatitis A , Linfocitos T , Receptor 2 Celular del Virus de la Hepatitis A/metabolismo , Humanos , Nefropatías Diabéticas/inmunología , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/patología , Femenino , Persona de Mediana Edad , Masculino , Animales , Ratones , Linfocitos T/inmunología , Linfocitos T/metabolismo , Anciano , Adulto , Inflamación/inmunología , Riñón/patología , Riñón/inmunología , Ratones Endogámicos C57BL , Progresión de la Enfermedad
3.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 49(1): 75-83, 2024 Jan 28.
Artículo en Inglés, Chino | MEDLINE | ID: mdl-38615169

RESUMEN

OBJECTIVES: With the in-depth study of complement dysregulation, glomerulonephritis with dominant C3 has received increasing attention, with a variety of pathologic types and large differences in symptoms and prognosis between pathologic types. This study analyzes the clinical, pathological, and prognostic characteristics of different pathological types of glomerulonephritis with dominant C3, aiming to avoid misdiagnosis and missed diagnoses. METHODS: The clinical, pathological, and follow-up data of 52 patients diagnosed as glomerulonephritis with dominant C3 by renal biopsy from June 2013 to October 2022 were retrospectively analyzed. According to the clinical feature and results of pathology, 15 patients with post-infectious glomerulonephritis (PIGN) and 37 patients with of non-infectious glomerulonephritis (N-PIGN) were classified. N-PIGN subgroup analysis was performed, and 16 patients were assigned into a C3-alone-deposition group and 21 in a C3-dominant-deposition group, or 27 in a C3 glomerulopathy (C3G) group and 10 in a non-C3 nephropathy (N-C3G) group. RESULTS: The PIGN group had lower creatinine values (84.60 µmol/L vs179.62 µmol/L, P=0.001), lower complement C3 values (0.36 g/L vs0.74 g/L, P<0.001) at biopsy, and less severe pathological chronic lesions compared with the N-PIGN group. In the N-PIGN subgroup analysis, the C3-dominant-deposition group had higher creatinine values (235.30 µmol/L vs106.70 µmol/L, P=0.004) and higher 24-hour urine protein values (4 025.62 mg vs1 981.11 mg, P=0.037) than the C3-alone-deposition group. The prognosis of kidney in the PIGN group (P=0.049), the C3-alone-deposition group (P=0.017), and the C3G group (P=0.018) was better than that in the N-PIGN group, the C3-dominant-deposition group, and the N-C3G group, respectively. CONCLUSIONS: Glomerulonephritis with dominant C3 covers a variety of pathological types, and PIGN needs to be excluded before diagnosing C3G because of considerable overlap with atypical PIGN and C3G; in addition, the deposition of C1q complement under fluorescence microscope may indicate poor renal prognosis, and relevant diagnosis, treatment, and follow-up should be strengthened.


Asunto(s)
Complemento C3 , Glomerulonefritis , Humanos , Creatinina , Estudios Retrospectivos , Glomerulonefritis/diagnóstico , Riñón
4.
Am J Transplant ; 2024 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-38648890

RESUMEN

The activation of innate immunity following transplantation has been identified as a crucial factor in allograft inflammation and rejection. However, the role of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)/stimulator of interferon genes (STING) signaling-mediated innate immunity in the pathogenesis of allograft rejection remains unclear. Utilizing a well-established murine model of corneal transplantation, we demonstrated increased expression of cGAS and STING in rejected-corneal allografts compared with syngeneic (Syn) and normal (Nor) corneas, along with significant activation of the cGAS/STING pathway, as evidenced by the enhanced phosphorylation of TANK-binding kinase 1and interferon regulatory factor 3. Pharmacological and genetic inhibition of cGAS/STING signaling markedly delayed corneal transplantation rejection, resulting in prolonged survival time and reduced inflammatory infiltration. Furthermore, we observed an increase in the formation of neutrophil extracellular traps (NETs) in rejected allografts, and the inhibition of NET formation through targeting peptidylarginine deiminase 4 and DNase I treatment significantly alleviated immune rejection and reduced cGAS/STING signaling activity. Conversely, subconjunctival injection of NETs accelerated corneal transplantation rejection and enhanced the activation of the cGAS/STING pathway. Collectively, these findings demonstrate that NETs contribute to the exacerbation of allograft rejection via cGAS/STING signaling, highlighting the targeting of the NETs/cGAS/STING signaling pathway as a potential strategy for prolonging allograft survival.

5.
Curr Med Chem ; 2024 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-38415439

RESUMEN

INTRODUCTION: Due to the confounding heterogeneity, the therapeutic strategy for proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) remains to be defined. CASE REPRESENTATION: We report a 38-year-old man with recurrent swelling of the eyelids and lower limbs, undergoing rituximab combined with steroid and tacrolimus treatment, who achieved an improved renal outcome. Underlying solid malignant tumours were excluded from the diagnosis. DISCUSSION: We treated patients with rituximab along with steroids and tacrolimus. Improvements in proteinuria and renal function were observed. We also reviewed the current literature to assess the efficacy of rituximab in the treatment of PGNMID. CONCLUSION: However, a larger pool of patients and a longer follow-up period are required to establish the role of rituximab and steroids in the treatment of PGNMID.

6.
Curr Med Chem ; 31(22): 3436-3446, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38299395

RESUMEN

BACKGROUND: Lipid metabolism imbalance is involved in the mechanism of renal tubular injury in diabetic kidney disease (DKD). Fatty acid binding protein 4 (FABP4) has been reported to participate in cellular lipid toxicity. However, the expression of FABP4 in renal tissues of DKD and its correlation with clinical/ pathological parameters and prognosis have not been studied. METHODS: A retrospective cohort study was conducted in 108 hospitalized Type 2 diabetes (T2D) patients with renal injury, including 70 with DKD and 38 with NDKD (non-DKD). Clinical features, pathological findings, and follow-up parameters were collected. Serum and urine FABP4 were detected by ELISA. An immunohistochemistry stain was used to determine FABP4 in renal tubulointerstitium. A double immunofluorescence stain was employed to assess FABP4- and CD68-positive macrophages. Correlation analysis, logistic regression models, receiver operating characteristic (ROC), and Kaplan-Meier survival curve were performed for statistical analysis. RESULTS: DKD patients had increased expression of FABP4 and ectopic fat deposition in tubules. As shown by correlation analyses, FABP4 expression in renal tubules was positively correlated with UNAG (r=0.589, p=0.044) and ESRD (r=0.740, p=0.004). Multivariate regression analysis revealed that UNAG level was correlated with FABP4 expression level above median value (odds ratio:1.154, 95% confidence interval:1.009-1.321, p=0.037). High-expression of FABP4 in renal tubules of DKD was at an increased risk of ESRD. Increased FABP4 expression in inflammatory cells was also associated with ESRD in DKD. CONCLUSION: High-expression of FABP4 is involved in the pathogenesis of renal tubular lipid injury and is a risk factor for poor prognosis in DKD patients.


Asunto(s)
Nefropatías Diabéticas , Proteínas de Unión a Ácidos Grasos , Túbulos Renales , Humanos , Proteínas de Unión a Ácidos Grasos/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Túbulos Renales/metabolismo , Túbulos Renales/patología , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Nefropatías Diabéticas/diagnóstico , Factores de Riesgo , Anciano , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/complicaciones
7.
J Med Virol ; 95(10): e29196, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37881096

RESUMEN

Kidney injury is common in patients with Coronavirus Disease-19 (COVID-19), which is related to poor prognosis. We aim to summarize the clinical features, athological types, and prognosis of COVID-19 associated kidney injury caused by the Omicron strain. In this study, 46 patients with Omicron-associated kidney injury were included, 38 of whom performed renal biopsy. Patients were divided into two groups: group A for patients with onset of kidney injury after SARS-CoV-2 infection; group B for patients with pre-existing kidney disease who experienced aggravation of renal insufficiency after SARS-CoV-2 infection. The clinical, pathological, and prognostic characteristics of the patients were observed. Acute kidney injury (AKI) (35%) was the most common clinical manifestation in group A. Patients in group B mainly presented with chronic kidney disease (CKD) (55%) and nephrotic syndrome (NS) (40%). The pathological type was mainly IgA nephropathy (IgAN) (39% in group A and 45% in group B). Among all of them, one case presenting with thrombotic microangiopathy had worse kidney function at biopsy time. Mean serum C3 levels were 1.2 ± 0.5 and 1.0 ± 0.2 g/L in group A and group B, respectively. In renal tissues, C3 deposits were observed in 71.1% of patients. 11.8% (n = 2) patients experienced deterioration of renal function after treatment, but no patients developed to end-stage renal disease. In our single-center study in China, the main clinical manifestations were AKI, CKD, and NS, while the main pathological type was IgAN. Compared with previous strains of SARS-CoV-2, patients with the Omicron infection had a favorable prognosis.


Asunto(s)
Lesión Renal Aguda , COVID-19 , Glomerulonefritis por IGA , Insuficiencia Renal Crónica , Humanos , SARS-CoV-2 , COVID-19/complicaciones , COVID-19/patología , Riñón/fisiología , Riñón/patología , Glomerulonefritis por IGA/complicaciones , Glomerulonefritis por IGA/patología , Lesión Renal Aguda/etiología , Lesión Renal Aguda/patología , Insuficiencia Renal Crónica/complicaciones , Estudios Retrospectivos
8.
Postgrad Med J ; 100(1179): 20-27, 2023 Dec 21.
Artículo en Inglés | MEDLINE | ID: mdl-37827532

RESUMEN

PURPOSE: To assess the regional epidemiological trends of kidney diseases over time in the South China using renal biopsy-proven cases. METHODS: This retrospective observational cohort study was conducted at the Institute of Nephrology, Second Xiangya Hospital of Central South University, and encompasses all patients diagnosed with kidney disease via biopsy from 2012 to 2021. RESULTS: The study sample consisted of 10 199 native kidneys, with a male-to-female ratio of 0.91:1 and an average age of 38.74 (±14.53) years. Primary glomerular nephropathy, systemic glomerular nephropathy (SGN), tubulointerstitial disease, and hereditary renal diseases accounted for 66.92 (6825)%, 24.49 (2498)%, 8.06 (822)%, and 0.53 (54)%, respectively. The leading pathologies of primary glomerular nephropathy remained the IgA nephropathy. The frequencies of IgA nephropathy and membranous nephropathy increased significantly, whereas the frequencies of minimal change disease and focal segmental glomerulosclerosis decreased (P < .001) between 2017 and 2021 than in the years 2012 and 2016. An earlier onset of membranous nephropathy was observed in the age group of 45-59 years compared to previous studies. The leading pathologies of SGN were found to be lupus nephritis (758 cases, 30.45%) and hypertension nephropathy (527 cases, 21.17%). The frequencies of hypertension nephropathy and diabetic nephropathy increased between 2017 and 2021 compared to 2012 and 2016 (P < .001), gradually becoming the leading pathological types of SGN. In elderly patients diagnosed with nephrotic syndrome, the frequencies of amyloidosis significantly increased (P < .01). CONCLUSION: Our study may provide insights for kidney disease prevention and public health strategies. What is already known on this topic The pathological spectrum of kidney diseases has undergone significant transformations in the past decade, driven by the escalating incidence of chronic diseases. Although there are studies exploring the renal biopsy findings from various regions in China which present both similarities and differences in epidemiology, few large-scale reports from the South China in recent decades were published. What this study adds Our findings reveal the following key observations: (i) increased proportion of middle-aged patients leading to the increasing average age at the time of biopsy;(ii) the frequencies of IgA nephropathy and membranous nephropathy (MN) increased significantly, whereas the frequencies of minimal change disease and focal segmental glomerulosclerosis decreased (P < .001) between 2017 and 2021 than in the years 2012 and 2016; (iii) earlier onset of MN in the age group of 45-59 years old was found in our study; and (iv) a higher frequency of hypertension nephropathy and DN presented over time, and frequency of amyloidosis increased in elderly patients diagnosed with NS. How this study might affect research, practice, or policy This single-center yet a large-scale study of the kidney disease spectrum in South China may provide a reference point for the diagnosis, treatment, and prevention of chronic kidney disease.


Asunto(s)
Amiloidosis , Glomerulonefritis por IGA , Glomerulonefritis Membranosa , Glomeruloesclerosis Focal y Segmentaria , Hipertensión Renal , Enfermedades Renales , Nefrosis Lipoidea , Persona de Mediana Edad , Anciano , Humanos , Masculino , Femenino , Adulto , Lactante , Glomerulonefritis Membranosa/epidemiología , Glomerulonefritis Membranosa/patología , Glomerulonefritis por IGA/epidemiología , Glomeruloesclerosis Focal y Segmentaria/epidemiología , Nefrosis Lipoidea/epidemiología , Estudios Retrospectivos , Enfermedades Renales/epidemiología , Biopsia , China/epidemiología
9.
Redox Biol ; 66: 102855, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37597421

RESUMEN

Peroxisomes are metabolically active organelles that are known for exerting oxidative metabolism, but the precise mechanism remains unclear in diabetic nephropathy (DN). Here, we used proteomics to uncover a correlation between the antioxidant protein disulfide-bond A oxidoreductase-like protein (DsbA-L) and peroxisomal function. In vivo, renal tubular injury, oxidative stress, and cell apoptosis in high-fat diet plus streptozotocin (STZ)-induced diabetic mice were significantly increased, and these changes were accompanied by a "ghost" peroxisomal phenotype, which was further aggravated in DsbA-L-deficient diabetic mice. In vitro, the overexpression of DsbA-L in peroxisomes could improve peroxisomal phenotype and function, reduce oxidative stress and cell apoptosis induced by high glucose (HG, 30 mM) and palmitic acid (PA, 250 µM), but this effect was reversed by 3-Amino-1,2,4-triazole (3-AT, a catalase inhibitor). Mechanistically, DsbA-L regulated the activity of catalase by binding to it, thereby reducing peroxisomal leakage and proteasomal degradation of peroxisomal matrix proteins induced by HG and PA. Additionally, the expression of DsbA-L in renal tubules of patients with DN significantly decreased and was positively correlated with peroxisomal function. Taken together, these results highlight an important role of DsbA-L in ameliorating tubular injury in DN by improving peroxisomal function.


Asunto(s)
Diabetes Mellitus Experimental , Nefropatías Diabéticas , Animales , Ratones , Catalasa , Peroxisomas , Estrés Oxidativo
10.
BMC Nephrol ; 24(1): 200, 2023 07 03.
Artículo en Inglés | MEDLINE | ID: mdl-37400798

RESUMEN

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening disorder characterized by systemic inflammation and organ failure as a result of dysregulated immune cell activation. HLH can be induced by a variety of factors including infection, tumours and autoimmune disease and can also occur in patients following solid organ transplantation. Occurrence of HLH and lupus nephritis (LN) successively within a short period of time after renal transplantation is uncommon. CASE PRESENTATION: We described an 11-year-old female post-transplant patient who presented with hemocytopenia, fever, elevated serum ferritin, splenomegaly, hyperlipidemia, and hypofibrinemia, and was clinically diagnosed with HLH. After comprehensive treatment with corticosteroids, intravenous immunoglobulin (IVIG), and reducing immunosuppressants, her condition improved, but then hematuria ensued. The transplant kidney biopsy showed LN. She was treated with hydroxychloroquine and methylprednisolone while intensive immunosuppressive agents were given. She has remained in remission for two years until now. CONCLUSIONS: The main inducing factors of HLH should be identified as early as possible, and accurate treatment plans should be taken. The long-course IVIG regimen may be one of the effective treatments for virus-induced HLH. After remission of HLH, we need to be alert to the recurrence of autoimmune diseases in patients with underlying diseases, and timely increase immunosuppressants.


Asunto(s)
Trasplante de Riñón , Nefritis Lúpica , Linfohistiocitosis Hemofagocítica , Virosis , Humanos , Niño , Femenino , Linfohistiocitosis Hemofagocítica/diagnóstico , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Linfohistiocitosis Hemofagocítica/etiología , Trasplante de Riñón/efectos adversos , Nefritis Lúpica/complicaciones , Nefritis Lúpica/diagnóstico , Nefritis Lúpica/tratamiento farmacológico , Inmunoglobulinas Intravenosas/uso terapéutico , Inmunosupresores/uso terapéutico , Riñón , Virosis/complicaciones
11.
Kidney Blood Press Res ; 48(1): 485-494, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37279699

RESUMEN

INTRODUCTION: Acute kidney injury (AKI) caused by cisplatin is common and has a higher incidence of multiple use, resulting in a poor short- and long-term prognosis for patients. There is currently no good premedication AKI risk assessment tool. The aim of this study was to establish an AKI risk assessment nomogram for patients with multiple cisplatin applications. METHODS: This study was a retrospective analysis of patients who were treated with non-first-time cisplatin chemotherapy regimen at Changzhou Second People's Hospital affiliated to Nanjing Medical University from January 2016 to January 2022. All data from the development group were used to screen the impact factors of AKI via univariate and multivariate analyses. A nomogram was developed based on these impact factors and verified with verification group. The area under the curve (AUC) of receiver operating characteristic (ROC) curve, calibration curves, and decision curve analyses (DCAs) were used to evaluate the nomogram. RESULTS: Among the 256 patients enrolled in 450 cycles of chemotherapy, 282 were in the development cohort (97 AKI), and 168 were in the validation cohort (61 AKI). Multivariate logistic regression revealed that age, hypertension, diabetes, serum cystatin C (sCysC), urinary kidney injury molecule-1 (uKim1), and a single dose of cisplatin were independently associated with AKI. The results showed that our model yielded satisfied diagnostic performance with an AUC value of 0.887 and 0.906 using the development group and on verification group. The calibration plots and DCA showed the superior clinical applicability of the nomogram. These results were verified in the validation cohort. CONCLUSION: A nomogram combining functional (sCysC) and tubular (uKim1) injury biomarkers with conventional clinical factors might assess the risk of AKI after multiple cycles of cisplatin chemotherapy.


Asunto(s)
Lesión Renal Aguda , Nomogramas , Humanos , Cisplatino/efectos adversos , Estudios Retrospectivos , Lesión Renal Aguda/diagnóstico , Medición de Riesgo
12.
Clin Sci (Lond) ; 137(12): 931-945, 2023 06 28.
Artículo en Inglés | MEDLINE | ID: mdl-37226722

RESUMEN

Mitochondria-associated endoplasmic reticulum membranes (MAMs) regulate ATG14- and Beclin1-mediated mitophagy and play key roles in the development of diabetic nephropathy (DN). DsbA-L is mainly located in MAMs and plays a role in renoprotection, but whether it activates mitophagy by maintaining MAM integrity remains unclear. In the present study, we found that renal tubular damage was further aggravated in diabetic DsbA-L-/- mice compared with diabetic mice and that this damage was accompanied by disrupted MAM integrity and decreased mitophagy. Furthermore, notably decreased expression of ATG14 and Beclin1 in MAMs extracted from the kidneys of diabetic DsbA-L-/- mice was observed. In vitro, overexpression of DsbA-L reversed the disruption of MAM integrity and enhanced mitophagy in HK-2 cells, a human proximal tubular cell line, after exposure to high-glucose (HG) conditions. Additionally, compared with control mice, DsbA-L-/- mice were exhibited down-regulated expression of helicase with zinc finger 2 (HELZ2) in their kidneys according to transcriptome analysis; HELZ2 serves as a cotranscription factor that synergistically functions with PPARα to promote the expression of mitofusin 2 (MFN-2). Treatment of HK-2 cells with MFN-2 siRNA resulted in MAM uncoupling and decreased mitophagy. Moreover, HG notably reduced the expression of HELZ2 and MFN-2 and inhibited mitophagy, and these effects were partially blocked by overexpression of DsbA-L and altered upon cotreatment with HELZ2 siRNA, HELZ2 overexpression or MK886 (PPARα inhibitor) treatment. These data indicate that DsbA-L alleviates diabetic tubular damage by activating mitophagy through maintenance of MAM integrity via the HELZ2/MFN-2 pathway.


Asunto(s)
Diabetes Mellitus Experimental , Nefropatías Diabéticas , Ratones , Humanos , Animales , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/metabolismo , Diabetes Mellitus Experimental/metabolismo , Mitocondrias/metabolismo , Beclina-1/metabolismo , Beclina-1/farmacología , Mitofagia/genética , PPAR alfa/metabolismo , ARN Interferente Pequeño/metabolismo
13.
Ann Med ; 55(1): 2215538, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37246836

RESUMEN

OBJECTIVE: Bowman's capsule rupture (BCR) is a glomerular pathological change, but it is still not well recognized in immunoglobulin A vasculitis nephritis (IgAV-N). The Oxford MEST-C score is a classification for IgA nephropathy; however, its clinical correlation and prognostic value in adult patients with IgAV-N are unclear. METHODS: A retrospective study of 145 adult patients with IgAV-N diagnosed by renal biopsy was conducted. Clinical manifestations, pathological changes and the prognosis of IgAV-N patients were compared depending on the presence or absence of BCR, International Study of Kidney Disease in Children (ISKDC) classification and MEST-C score. The primary endpoint events were end-stage renal disease, renal replacement therapy and all-cause death. RESULTS: In total, 51 of 145 (35.17%) patients with IgAV-N presented with BCR. Patients with BCR had more proteinuria, lower serum albumin, and more crescents. Compared with IgAV-N patients with crescents only, 51/100 patients with crescents combined with BCR had a higher proportion of crescents in all glomeruli (15.79% vs. 9.09%; p = 0.003). Patients with higher ISKDC grades had more severe clinical presentation, but it did not reflect the prognosis. However, the MEST-C score not only reflected clinical manifestations but also predicted prognosis (p < 0.05). BCR contributed to the effectiveness of the MEST-C score in predicting the prognosis of IgAV-N (C-index: 0.845 to 0.855). CONCLUSIONS: BCR is associated with clinical manifestations and pathological changes in patients with IgAV-N. The ISKDC classification and MEST-C score are related to the patient's condition, but only the MEST-C score is correlated with the prognosis of patients with IgAV-N, while BCR can improve its predictive ability.


BCR was associated with clinical manifestations and pathological changes in patients with IgAV-N, particularly crescents.The ISKDC classification was related to clinical manifestations of patients with IgAV-N, but it wasn't associated with prognosis.The Oxford MEST-C score was correlated to clinical presentations and prognosis of patients with IgAV-N, while BCR can improve its predictive ability.


Asunto(s)
Cápsula Glomerular , Vasculitis por IgA , Humanos , Adulto , Cápsula Glomerular/patología , Riñón/patología , Riñón/fisiopatología , Estudios Retrospectivos , Vasculitis por IgA/patología , Masculino , Femenino , Esclerosis/patología , Inflamación/patología , Pronóstico , Análisis de Supervivencia
14.
Int J Biol Macromol ; 236: 123959, 2023 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-36898464

RESUMEN

Sorbitol is commonly used in semi-dried noodles for holding water, thus extending the shelf life. This research analyzed the effect of sorbitol on the in vitro starch digestibility in semi-dried black highland barley noodles (SBHBN). In vitro starch digestion revealed that the hydrolysis extent and digestive rate decreased with increasing sorbitol addition, although its inhibition abated when added >2 %. Compared with the control, adding 2 % of sorbitol lowered the equilibrium hydrolysis (C∞) significantly (P < 0.05) from 75.18 to 66.57 % and decreased the kinetic coefficient (k) significantly (P < 0.05) by 20.29 %. Adding sorbitol increased the tightness of microstructure, relative crystallinity, V-type crystal, molecular structure order, and hydrogen bond strength of starch in cooked SBHBN. Meanwhile, gelatinization enthalpy change (ΔH) of starch in raw SBHBN was increased by adding sorbitol. In addition, the swelling power and amylose leaching in SBHBN added with sorbitol were reduced. Pearson correlations analysis observed significant (P < 0.05) correlations among short-range ordered structure, ΔH, and related in vitro starch digestion indexes of SBHBN after being added with sorbitol. These results revealed that sorbitol might form hydrogen bonds with starch, making it a potential additive to lower the eGI in starchy foods.


Asunto(s)
Hordeum , Almidón , Almidón/química , Digestión , Alimentos , Amilosa/química
15.
BMC Cardiovasc Disord ; 23(1): 127, 2023 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-36890445

RESUMEN

BACKGROUND: Left ventricular hypertrophy (LVH) and carotid atherosclerosis (CAS) have been identified as factors associated with cognitive impairment (CI) but have not been studied in patients undergoing peritoneal dialysis (PD). This study investigated the relationship between LVH and CAS and cognitive function in patients undergoing PD. METHODS: In this single-center cross-sectional study, the clinically stable patients who were over 18 years of age and had undergone PD for at least 3 months were enrolled. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA), which included seven areas: visuospatial/executive function, naming, attention, language, abstraction, delayed recall, and orientation. LVH was defined as LVMI > 46.7 g/m2.7 in women and LVMI > 49.2 g/m2.7 in men. CAS was defined as carotid intima-media thickness ≥ 1.0 mm and/or the presence of plaque. RESULTS: A total of 207 patients undergoing PD were recruited, with an average age of 52.14 ± 14.93 years and a median PD duration of 8 months (5-19 months). The CI rate was 56%, and the prevalence of CAS was 53.6%. LVH occurred in 110 patients (53.1%). Patients in the LVH group tended to be older, and had a higher body mass index, a higher pulse pressure, a higher male proportion, a lower ejection fraction, a higher prevalence of cardiovascular disease and CI, and a lower MoCA scores.Multivariate logistic regression analysis was conducted to analyze the association between LVH and CI (OR, 10.087; 95% confidence interval, 2.966-34.307). And the association between LVH and CI was still supported after propensity matching scores. CAS was not significantly associated with CI. CONCLUSION: LVH is independently associated with CI in patients undergoing PD, while CAS is not significantly associated with CI.


Asunto(s)
Enfermedades de las Arterias Carótidas , Disfunción Cognitiva , Diálisis Peritoneal , Humanos , Masculino , Femenino , Adolescente , Adulto , Persona de Mediana Edad , Anciano , Grosor Intima-Media Carotídeo , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/epidemiología , Estudios Transversales , Diálisis Peritoneal/efectos adversos , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/epidemiología , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/etiología
16.
Biol Res ; 56(1): 5, 2023 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-36732854

RESUMEN

BACKGROUND: Alpha-kinase 1 (ALPK1) is a master regulator in inflammation and has been proved to promote renal fibrosis by promoting the production of IL-1ß in diabetic nephropathy (DN) mice. Pyroptosis is involved in high glucose (HG)-induced tubular cells injury, characterized by activation of Gasdermin D (GSDMD) and the release of IL-1ß and IL-18, resulting in inflammatory injury in DN. It is reasonable to assume that ALPK1 is involved in pyroptosis-related tubular injury in DN. However, the mechanism remains poorly defined. METHODS: Immunohistochemistry (IHC) staining was performed to detect the expression of pyroptosis- and fibrosis-related proteins in renal sections of DN patients and DN mice. DN models were induced through injection of streptozotocin combined with a high-fat diet. Protein levels of ALPK1, NF-κB, Caspase-1, GSDMD, IL-1ß, IL-18 and α-SMA were detected by Western blot. HK-2 cells treated with high-glucose (HG) served as an in vitro model. ALPK1 small interfering RNA (siRNA) was transfected into HK-2 cells to down-regulate ALPK1. The pyroptosis rates were determined by flow cytometry. The concentrations of IL-1ß and IL-18 were evaluated by ELISA kits. Immunofluorescence staining was used to observe translocation of NF-κB and GSDMD. RESULTS: The heat map of differentially expressed genes showed that ALPK1, Caspase-1 and GSDMD were upregulated in the DN group. The expression levels of ALPK1, Caspase-1, GSDMD and CD68 were increased in renal biopsy tissues of DN patients by IHC. ALPK1expression and CD68+ macrophages were positively correlated with tubular injury in DN patients. Western blot analysis showed increased expressions of ALPK1, phospho-NF-κB P65, GSDMD-NT, and IL-1ß in renal tissues of DN mice and HK-2 cells, accompanied with increased renal fibrosis-related proteins (FN, α-SMA) and macrophages infiltration in interstitial areas. Inhibition of ALPK1 attenuated HG-induced upregulation expressions of NF-κB, pyroptosis-related proteins Caspase-1, GSDMD-NT, IL-1ß, IL-18, α-SMA, and pyroptosis level in HK-2 cells. Also, the intensity and nuclear translocation of NF-κB and membranous translocation of GSDMD were ameliorated in HG-treated HK-2 cells after treatment with ALPK1 siRNA. CONCLUSIONS: Our data suggest that ALPK1/NF-κB pathway initiated canonical caspase-1-GSDMD pyroptosis pathway, resulting in tubular injury and interstitial inflammation of DN.


Asunto(s)
Diabetes Mellitus , Nefropatías Diabéticas , Animales , Ratones , Caspasas , Fibrosis , Glucosa , Inflamación , Interleucina-18 , FN-kappa B/metabolismo , Piroptosis , ARN Interferente Pequeño
17.
Eur J Immunol ; 53(4): e2250109, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36781170

RESUMEN

T and B cells participate in the development of systemic lupus erythematosus (SLE). BTB and CNC homology 2 (Bach2) is an irreplaceable regulator in the T and B lineages that helps to maintain immune homeostasis. However, the function of Bach2 in the pathogenesis of SLE has not been studied in depth. Flow cytometry and qRT-PCR were used to assess Bach2 levels, bisulfite sequencing PCR was used to measure the methylation level, and silencing by electroporation and stimulation with a cytokine concentration gradient were used to investigate the effect of Bach2 on T cells. Bach2 expression was elevated in the helper T-cell subsets (T follicular helper, Th1, Th2, Th17, and Treg cells) of SLE patients and negatively correlated with disease severity and autoantibody levels. CD4+ T cells from SLE patients had decreased methylation levels in the Bach2 promoter region. Silencing Bach2 in CD4+ T cells induced increases in the CD19+ B-cell count, plasmablasts, and secretion of IgG by prompting the secretion of cytokines. The activation signals CD3/CD28, IL-6, and IL-21 upregulated Bach2 expression in CD4+ T cells. The regulation of Bach2 by cytokines and T-cell activation signals in CD4+ T cells was shown to act on B cells and play a protective role against SLE.


Asunto(s)
Citocinas , Lupus Eritematoso Sistémico , Humanos , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Diferenciación Celular , Inmunoglobulina G , Subgrupos de Linfocitos T , Linfocitos T Reguladores , Linfocitos T CD4-Positivos , Linfocitos B
18.
Biol. Res ; 56: 5-5, 2023. ilus, graf
Artículo en Inglés | LILACS | ID: biblio-1429906

RESUMEN

BACKGROUND: Alpha-kinase 1 (ALPK1) is a master regulator in inflammation and has been proved to promote renal fibrosis by promoting the production of IL-1ß in diabetic nephropathy (DN) mice. Pyroptosis is involved in high glucose (HG)-induced tubular cells injury, characterized by activation of Gasdermin D (GSDMD) and the release of IL-1ß and IL-18, resulting in inflammatory injury in DN. It is reasonable to assume that ALPK1 is involved in pyroptosis-related tubular injury in DN. However, the mechanism remains poorly defined. METHODS: Immunohistochemistry (IHC) staining was performed to detect the expression of pyroptosis- and fibrosis-related proteins in renal sections of DN patients and DN mice. DN models were induced through injection of streptozotocin combined with a high-fat diet. Protein levels of ALPK1, NF-κB, Caspase-1, GSDMD, IL-1ß, IL-18 and α-SMA were detected by Western blot. HK-2 cells treated with high-glucose (HG) served as an in vitro model. ALPK1 small interfering RNA (siRNA) was transfected into HK-2 cells to down-regulate ALPK1. The pyroptosis rates were determined by flow cytometry. The concentrations of IL-1ß and IL-18 were evaluated by ELISA kits. Immunofluorescence staining was used to observe translocation of NF-κB and GSDMD. RESULTS: The heat map of differentially expressed genes showed that ALPK1, Caspase-1 and GSDMD were upregulated in the DN group. The expression levels of ALPK1, Caspase-1, GSDMD and CD68 were increased in renal biopsy tissues of DN patients by IHC. ALPK1expression and CD68+ macrophages were positively correlated with tubular injury in DN patients. Western blot analysis showed increased expressions of ALPK1, phospho-NF-κB P65, GSDMD-NT, and IL-1ß in renal tissues of DN mice and HK-2 cells, accompanied with increased renal fibrosis-related proteins (FN, α-SMA) and macrophages infiltration in interstitial areas. Inhibition of ALPK1 attenuated HG-induced upregulation expressions of NF-κB, pyroptosis-related proteins Caspase-1, GSDMD-NT, IL-1ß, IL-18, α-SMA, and pyroptosis level in HK-2 cells. Also, the intensity and nuclear translocation of NF-κB and membranous translocation of GSDMD were ameliorated in HG-treated HK-2 cells after treatment with ALPK1 siRNA. CONCLUSIONS: Our data suggest that ALPK1/NF-κB pathway initiated canonical caspase-1-GSDMD pyroptosis pathway, resulting in tubular injury and interstitial inflammation of DN.


Asunto(s)
Animales , Ratones , Diabetes Mellitus , Nefropatías Diabéticas , Fibrosis , FN-kappa B/metabolismo , Caspasas , Interleucina-18 , ARN Interferente Pequeño , Piroptosis , Glucosa , Inflamación
19.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 47(10): 1365-1374, 2022 Oct 28.
Artículo en Inglés, Chino | MEDLINE | ID: mdl-36411687

RESUMEN

OBJECTIVES: Tubulointerstitial diseases is one of the common causes of renal dysfunction. Some rare pathological types are easy to be misdiagnosed and missedly diagnosed because of their low prevalence and relatively insufficient understanding, which affects the treatment and prognosis of patients. This study aims to explore clinical manifestations and pathological characteristics of several rare tubulointerstitial diseases, and therefore to improve their diagnosis and treatment. METHODS: A total of 9 363 patients diagnosed by renal biopsy in the Department of Nephrology, Second Xiangya Hospital, Central South University from November 2011 to September 2021 were selected. Six cases of light chain cast nephropathy (LCCN), 2 cases of light chain proximal tubulopathy (LCPT), 1 case of LCCN with LCPT, 4 cases of genetic tubulointerstitial disease, and 6 cases of non-genetic related tubulointerstitial lesion were screened out, and their clinical manifestations and renal biopsy pathological results were collected, compared, and analyzed. RESULTS: Patients with LCCN presented with mild to moderate anemia, microscopic hematuria, and mild to moderate proteinuria. Compared with patients with LCPT, proteinuria and anemia were more prominent in patients with LCCN. Five patients with LCCN and 2 patients with LCPT had elevated serum free kappa light chain. Five patients with LCCN presented clinically with acute kidney injury (AKI). Two patients with LCPT and 1 patient with LCCN and LCPT showed CKD combined with AKI, and 1 LCPT patient presented with typical Fanconi syndrome (FS). Five patients with LCCN, 2 patients with LCPT, and 1 patient with LCCN and LCPT were diagnosed with multiple myeloma. Five patients with LCCN had kappa light chain restriction in tubules on immunofluorescence and a "fractured" protein casts with pale periodic acid-Schiff (PAS) staining on light microscopy. Immunohistochemical staining of 2 LCPT patients showed strongly positive kappa light chain staining in the proximal tubular epithelial cells. And monoclonal light chain crystals in crystalline LCPT and abnormal lysosomes and different morphological inclusion bodies in noncrystalline LCPT were observed under the electron microscope. Six patients with LCCN were mainly treated by chemotherapy. Renal function was deteriorated in 1 patient, was stable in 4 patients, and was improved in 1 patient. Two patients with LCPT improved their renal function after chemotherapy. Four patients with genetic tubulointerstitial disease were clinically presented as CKD, mostly mild proteinuria, with or without microscopic hematuria, and also presented with hyperuricemia, urine glucose under normal blood glucose, anemia, polycystic kidneys. Only 1 case had a clear family history, and the diagnosis was mainly based on renal pathological characteristics and genetic testing. Compared with patients with non-genetic related tubulointerstitial lesion, patients with genetic tubulointerstitial disease had an earlier age of onset, higher blood uric acid, lower Hb and estiated glomemlar fitration (eGFR), and less edema and hypertension. Renal pathology of genetic tubulointerstitial disease presented tubular atrophy and interstitial fibrosis, abnormal tubular dilation, glomerular capsuledilation, and glomerular capillary loop shrinkage. Glomerular dysplasia and varying degrees of glomerular sclerosis were observed. Genetic tubulointerstitial disease patients were mainly treated with enteral dialysis, hypouricemic and hypoglycemic treatment. Two genetic tubulointerstitial disease patients had significantly deteriorated renal function, and 2 patients had stable renal function. CONCLUSIONS: Patients with AKI or FS, who present serum immunofixation electrophoresis and/or serum free kappa light chain abnormalities, should be alert to LCCN or LCPT. Renal biopsy is a critical detection for diagnosis of LCCN and LCPT. Chemotherapy and stem cell transplantation could delay progression of renal function in patients with LCCN and LCPT. If the non-atrophic area of the renal interstitium presents glomerular capsule dilatation, glomerular capillary loop shrinkage, and abnormal tubular dilatation under the light microscopy, genetic tubulointerstitial disease might be considered, which should be traced to family history and can be diagnosed by genetic testing.


Asunto(s)
Lesión Renal Aguda , Anemia , Mieloma Múltiple , Nefritis Intersticial , Insuficiencia Renal Crónica , Humanos , Hematuria , Cadenas Ligeras de Inmunoglobulina/análisis , Proteinuria
20.
Cell Biosci ; 12(1): 175, 2022 Oct 18.
Artículo en Inglés | MEDLINE | ID: mdl-36258228

RESUMEN

BACKGROUND: The human endometrium is a highly regenerative tissue that is believed to have two main types of stem cells: endometrial mesenchymal/stromal stem cells (eMSCs) and endometrial epithelial stem cells (eESCs). So far, eMSCs have been extensively studied, whereas the studies of eESCs are constrained by the inability to culture and expand them in vitro. The aim of this study is to establish an efficient method for the production of eESCs from human endometrium for potential clinical application in intrauterine adhesion (IUA). RESULTS: Here we developed a culture condition with a combination of some small molecules for in vitro culturing and expansion of human SSEA-1+ cells. The SSEA-1+ cells exhibited stem/progenitor cell activity in vitro, including clonogenicity and differentiation capacity into endometrial epithelial cell-like cells. In addition, the SSEA-1+ cells, embedded in extracellular matrix, swiftly self-organized into organoid structures with long-term expansion capacity and histological phenotype of the human endometrial epithelium. Specifically, we found that the SSEA-1+ cells showed stronger therapeutic potential than eMSCs for IUA in vitro. In a rat model of IUA, in situ injection of the SSEA-1+ cells-laden chitosan could efficiently reduce fibrosis and facilitate endometrial regeneration. CONCLUSIONS: Our work demonstrates an approach for isolation and expansion of human eESCs in vitro, and an appropriate marker, SSEA-1, to identify eESCs. Furthermore, the SSEA-1+ cells-laden chitosan might provide a novel cell-based approach for IUA treatment. These findings will advance the understanding of pathophysiology during endometrial restoration which may ultimately lead to more rational clinical practice.

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