RESUMEN

[This corrects the article DOI: 10.3389/fneph.2023.1194989.].

RESUMEN

AIM: Mitochondrial dysfunction, a characteristic pathological feature of renal Ischemic/reperfusion injury (I/RI), predisposes tubular epithelial cells to maintain an inflammatory microenvironment, however, the exact mechanisms through which mitochondrial dysfunction modulates the induction of tubular injury remains incompletely understood. METHODS: ESI-QTRAP-MS/MS approach was used to characterize the targeted metabolic profiling of kidney with I/RI. Tubule injury, mitochondrial dysfunction, and fumarate level were evaluated using qPCR, transmission electron microscopy, ELISA, and immunohistochemistry. RESULTS: We demonstrated that tubule injury occurred at the phase of reperfusion in murine model of I/RI. Meanwhile, enhanced glycolysis and mitochondrial dysfunction were found to be associated with tubule injury. Further, we found that tubular fumarate, which resulted from fumarate hydratase deficiency and released from dysfunctional mitochondria, promoted tubular injury. Mechanistically, fumarate induced tubular injury by causing disturbance of glutathione (GSH) hemostasis. Suppression of GSH with buthionine sulphoximine administration could deteriorate the fumarate inhibition-mediated tubule injury recovery. Reactive oxygen species/NF-κB signaling activation played a vital role in fumarate-mediated tubule injury. CONCLUSION: Our studies demonstrated that the mitochondrial-derived fumarate promotes tubular epithelial cell injury in renal I/RI. Blockade of fumarate-mediated ROS/NF-κB signaling activation may serve as a novel therapeutic approach to ameliorate hypoxic tubule injury.

Asunto(s)

Lesión Renal Aguda , Enfermedades Mitocondriales , Daño por Reperfusión , Ratones , Animales , FN-kappa B/metabolismo , Espectrometría de Masas en Tándem , Riñón/metabolismo , Mitocondrias/metabolismo , Daño por Reperfusión/metabolismo , Reperfusión , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/patología , Isquemia/patología , Apoptosis

RESUMEN

Introduction: SARS-CoV-2 infection in the pediatric population can be associated with a multiorgan inflammatory syndrome called children's multisystem inflammatory syndrome (MIS-C). The kidneys can be affected by a broad spectrum of possible injuries, whose pathogenetic mechanisms are still unclear.Case report: We report the case of a 5-year-old boy with severe cardiac involvement in the context of MIS-C. After two weeks of hospitalization, an abdominal ultrasound showed massive bladder "debris", followed by the onset of normoglycemic glycosuria. Over time, there was a progressive increase in glycosuria, and the presence of a mat of amorphous phosphate crystals was evidenced on urinary sediment. Together with the findings of hypo-uricemia, increased urinary uric acid, and globally increased urinary amino acids, a clinical picture of kidney proximal tubular damage with secondary Fanconi-like syndrome took shape. Discussion: This case report describes the case of a patient with MIS-C with cardiac and kidney involvement characterized by proximal tubular damage, which slowly improved but still persisted at the 8-month follow-up. The pathogenesis of the damage is unclear and probably multifactorial.

RESUMEN

Vitamin A (VA, retinol) and its metabolites (commonly called retinoids) are required for the proper development of the kidney during embryogenesis, but retinoids also play key roles in the function and repair of the kidney in adults. Kidneys filter 180-200 liters of blood per day and each kidney contains approximately 1 million nephrons, which are often referred to as the 'functional units' of the kidney. Each nephron consists of a glomerulus and a series of tubules (proximal tubule, loop of Henle, distal tubule, and collecting duct) surrounded by a network of capillaries. VA is stored in the liver and converted to active metabolites, most notably retinoic acid (RA), which acts as an agonist for the retinoic acid receptors ((RARs α, ß, and γ) to regulate gene transcription. In this review we discuss some of the actions of retinoids in the kidney after injury. For example, in an ischemia-reperfusion model in mice, injury-associated loss of proximal tubule (PT) differentiation markers occurs, followed by re-expression of these differentiation markers during PT repair. Notably, healthy proximal tubules express ALDH1a2, the enzyme that metabolizes retinaldehyde to RA, but transiently lose ALDH1a2 expression after injury, while nearby myofibroblasts transiently acquire RA-producing capabilities after injury. These results indicate that RA is important for renal tubular injury repair and that compensatory mechanisms exist for the generation of endogenous RA by other cell types upon proximal tubule injury. ALDH1a2 levels also increase in podocytes, epithelial cells of the glomeruli, after injury, and RA promotes podocyte differentiation. We also review the ability of exogenous, pharmacological doses of RA and receptor selective retinoids to treat numerous kidney diseases, including kidney cancer and diabetic kidney disease, and the emerging genetic evidence for the importance of retinoids and their receptors in maintaining or restoring kidney function after injury. In general, RA has a protective effect on the kidney after various types of injuries (eg. ischemia, cytotoxic actions of chemicals, hyperglycemia related to diabetes). As more research into the actions of each of the three RARs in the kidney is carried out, a greater understanding of the actions of vitamin A is likely to lead to new insights into the pathology of kidney disorders and the development of new therapies for kidney diseases.

Asunto(s)

Riñón , Retinoides , Vitamina A , Vitamina A/metabolismo , Riñón/fisiología , Retinoides/metabolismo , Receptores de Ácido Retinoico/metabolismo , Tretinoina/metabolismo , Enfermedades Renales/metabolismo

RESUMEN

Tubule injury is a characteristic pathological feature of acute kidney injury (AKI) and determines the prognosis of kidney disease. However, the exact mechanism of tubule injury remains largely unclear. In the present study, the exact mechanism of tubule injury was investigated. Bilateral renal ischemia/reperfusion (I/R) injury (I/RI) was induced in mice and exosome secretion inhibitor GW4869 and miRNA­155 inhibitor were used. In addition, the exosomal microRNA (miR)­155­mediated cross­talk between macrophage and tubular cells was also investigated. It was determined that tubular injury was observed in an I/R­induced AKI model, which was closely associated with macrophage infiltration. Interestingly, blocking exosome production using GW4869 ameliorated tubular injury in I/R­induced AKI. Mechanistically, once released, activated macrophage­derived exosomal miR­155 was internalized by tubular cells, resulting in increased tubule injury through targeting of suppressor of cytokine signaling­1 (SOCS­1), a negative regulator of NF­κB signaling. In addition, a dual­luciferase reporter assay confirmed that SOCS­1 was the direct target of miR­155 in tubular cells. Notably, injection of these miR­155­enriched exosomes into renal parenchyma resulted in increased tubule injury in vivo. Thus, the present study demonstrated that exosomal miR­155 mediated the communication between activated macrophages and injured tubules, leading to progression of AKI, which not only provide novel insights into the pathophysiology of AKI but also offer a new therapeutic strategy for kidney diseases.

Asunto(s)

Lesión Renal Aguda , Exosomas , Macrófagos , MicroARNs , Daño por Reperfusión , Lesión Renal Aguda/genética , Lesión Renal Aguda/patología , Animales , Exosomas/genética , Isquemia , Túbulos Renales/patología , Macrófagos/patología , Ratones , MicroARNs/genética , Daño por Reperfusión/complicaciones , Daño por Reperfusión/genética , Daño por Reperfusión/patología , Proteínas Supresoras de la Señalización de Citocinas

Asunto(s)

Lesión Renal Aguda , Organoides , Humanos , Riñón , Túbulos Renales Proximales

RESUMEN

Diabetic kidney disease (DKD) is a devastating microvascular complication associated with diabetes mellitus. Recently, the major focus of glomerular lesions of DKD has partly shifted to diabetic tubulopathy because of renal insufficiency and prognosis of patients is closely related to tubular atrophy and interstitial fibrosis. Indeed, the proximal tubule enriching in mitochondria for its high energy demand and dependence on aerobic metabolism has given us pause to focus primarily on the mitochondria-centric view of early diabetic tubulopathy. Multiple studies suggest that diabetes condition directly damages renal tubules, resulting in mitochondria dysfunction, including decreased bioenergetics, overproduction of mitochondrial reactive oxygen species (mtROSs), defective mitophagy and dynamics disturbances, which in turn trigger a series of metabolic abnormalities. However, the precise mechanism underlying mitochondrial dysfunction of renal tubules is still in its infancy. Understanding tubulointerstitial's pathobiology would facilitate the search for new biomarkers of DKD. In this Review, we summarize the current literature and postulate that the potential effects of mitochondrial dysfunction may accelerate initiation of early-stage diabetic tubulopathy, as well as their potential therapeutic strategies.

Asunto(s)

Diabetes Mellitus , Nefropatías Diabéticas , Diabetes Mellitus/metabolismo , Nefropatías Diabéticas/metabolismo , Femenino , Humanos , Túbulos Renales/metabolismo , Túbulos Renales Proximales/metabolismo , Masculino , Mitocondrias/metabolismo , Especies Reactivas de Oxígeno/metabolismo

RESUMEN

We attempted to analyze the clinical value of microRNA (miR)-590-3p in diabetic nephropathy (DN) patients and its role in high glucose (HG)-induced renal tubular epithelial cell (HK-2) injury. Serum levels of miR-590-3p were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Spearman correlation coefficient analysis of the correlation between miR-590-3p and clinical indicators. The diagnostic value of miR-590-3p was analyzed by the receiver operating characteristic (ROC) curve. Then, the DN cell model induced by HG in HK-2 cells was established. Enzyme-linked immunosorbent assay (ELISA), flow cytometry, and CCK-8 assay were employed to assess cell inflammation, oxidative stress, apoptosis, and proliferation. Dual-luciferase reporter assay confirmed the target of miR-590-3p. Serum miR-590-3p was reduced in patients of DN, which was positively correlated with eGFR and negatively associated with albuminuria. Furthermore, miR-590-3p also can diagnose patients of DN from healthy subjects or patients of T2DM. Furthermore, miR-590-3p was decreased in a concentration- and time-dependent manner during HG-induction. miR-590-3p overexpression bated HG-induced inhibition effect on cell proliferation and promotion effects on apoptosis, oxidative stress, and inflammation. C-X3-C motif chemokine ligand1 (CX3CL1) is the target of miR-590-3p, whose levels were enhanced in DN patients and are negatively regulated by miR-590-3p. Our discoveries offered new insights that reduced miR-590-3p as a potential biomarker for the diagnosis of DN, and elevated miR-590-3p can alleviate renal tubular injury by HG-induced through targeting CX3XL1, which may be a novel target for improving the development of DN.

Asunto(s)

Quimiocina CX3CL1/metabolismo , Nefropatías Diabéticas/metabolismo , Células Epiteliales/metabolismo , Glucosa/metabolismo , Túbulos Renales/metabolismo , MicroARNs/metabolismo , Adulto , Anciano , Línea Celular , Femenino , Humanos , Masculino , Persona de Mediana Edad

RESUMEN

RATIONALE & OBJECTIVE: Most circulating biomarkers of chronic kidney disease (CKD) progression focus on factors reflecting glomerular filtration. Few biomarkers capture nonglomerular pathways of kidney injury or damage, which may be particularly informative in populations at high risk for CKD progression such as individuals with diabetes. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: 594 participants (mean age, 70 years; 53% women) of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study who had diabetes and an estimated glomerular filtration rate (eGFR)<60mL/min/1.73m2 at baseline. EXPOSURES: Plasma biomarkers of inflammation/fibrosis (TNFR1 and TNFR2, suPAR, MCP-1, YKL-40) and tubular injury (KIM-1) measured at the baseline visit. OUTCOMES: Incident kidney failure with replacement therapy (KFRT). ANALYTICAL APPROACH: Cox proportional hazards regression and least absolute shrinkage and selection operator regression adjusted for established risk factors for kidney function decline, baseline eGFR, and urinary albumin-creatinine ratio (UACR). RESULTS: A total of 98 KFRT events were observed over a mean of 6.2±3.5 (standard deviation) years of follow-up. Plasma biomarkers were modestly associated with baseline eGFR (correlation coefficients ranging from-0.08 to-0.65) and UACR (0.14 to 0.56). In individual biomarker models adjusted for eGFR, UACR, and established risk factors, hazard ratios for incident KFRT per 2-fold higher biomarker concentrations were 1.52 (95% CI, 1.25-1.84) for plasma KIM-1, 1.54 (95% CI, 1.08-2.21) for TNFR1, 1.91 (95% CI, 1.16-3.14) for TNFR2, and 1.39 (95% CI, 1.05-1.84) for YKL-40. In least absolute shrinkage and selection operator regression models accounting for biomarkers in parallel, plasma KIM-1 and TNFR1 remained associated with incident KFRT. LIMITATIONS: Single biomarker measurement, lack of follow-up eGFR assessments. CONCLUSIONS: Individual plasma markers of inflammation/fibrosis (TNFR1, TNFR2, YKL-40) and tubular injury (KIM-1) were associated with risk of incident KFRT in adults with diabetes and an eGFR<60mL/min/1.73m2 after adjustment for established risk factors.

Asunto(s)

Diabetes Mellitus , Nefropatías Diabéticas , Insuficiencia Renal Crónica , Adulto , Anciano , Biomarcadores , Proteína 1 Similar a Quitinasa-3 , Estudios de Cohortes , Nefropatías Diabéticas/diagnóstico , Nefropatías Diabéticas/etiología , Progresión de la Enfermedad , Femenino , Fibrosis , Tasa de Filtración Glomerular , Humanos , Inflamación , Riñón/metabolismo , Masculino , Receptores Tipo I de Factores de Necrosis Tumoral , Receptores Tipo II del Factor de Necrosis Tumoral , Insuficiencia Renal Crónica/metabolismo

RESUMEN

Obesity increases the risk of other diseases, including kidney disease. Local renal tubular renin-angiotensin system (RAS) activation may play a role in obesity-associated kidney disease. Extracellular vehicles (EVs) transmit necessary information in obesity and cause remote organ damage, but the mechanism is unclear. The aim of the study was to investigate whether the plasma EVs cargo miR-6869-5p causes RAS activation and renal tubular damage. We isolated plasma EVs from obese and lean subjects and analyzed differentially-expressed miRNAs using RNA-seq. Then, EVs were co-cultured with human proximal renal tubular epithelial cells (PTECs) in vitro. Immunohistochemical pathology was used to assess the degree of RAS activation and tubule injury in vivo. The tubule damage-associated protein and RAS activation components were detected by Western blot. Obesity led to renal tubule injury and RAS activation in humans and mice. Obese-EVs induce RAS activation and renal tubular injury in PTECs. Importantly, miR-6869-5p-treated PTECs caused RAS activation and renal tubular injury, similar to Obese-EVs. Inhibiting miR-6869-5p decreased RAS activation and renal tubular damage. Our findings indicate that plasma Obese-EVs induce renal tubule injury and RAS activation via miR-6869-5p transport. Thus, miR-6869-5p in plasma Obese-EVs could be a therapeutic target for local RAS activation in obesity-associated kidney disease.

RESUMEN

For over 70 years, serum creatinine has remained the primary index for detection and monitoring of kidney disease. Tubulointerstitial damage and fibrosis are highly prognostic for subsequent kidney failure in biopsy studies, yet this pathology is invisible to the clinician in the absence of a biopsy. Recent discovery of biomarkers that reflect distinct aspects of kidney tubule disease have led to investigations of whether these markers can provide additional information on risk of chronic kidney disease (CKD) progression and associated adverse clinical end points, above and beyond estimated glomerular filtration rate and albuminuria. These biomarkers can be loosely grouped into those that mark tubule cell injury (eg, kidney injury molecule 1, monocyte chemoattractant protein 1) and those that mark tubule cell dysfunction (eg, α1-microglobulin, uromodulin). These kidney tubule biomarkers provide new opportunities to monitor response to therapeutics used to treat CKD patients. In this review, we describe results from some unique contributions in this area and discuss the current challenges and requirements in the field to bring these markers to clinical practice. We advocate for a broader assessment of kidney health that moves beyond a focus on the glomerulus, and we highlight how such tools can improve diagnostic accuracy and earlier assessment of therapeutic efficacy or harm in CKD patients.

Asunto(s)

Insuficiencia Renal Crónica , Albuminuria , Biomarcadores , Tasa de Filtración Glomerular , Humanos , Túbulos Renales , Insuficiencia Renal Crónica/diagnóstico

RESUMEN

RATIONALE & OBJECTIVE: The associations of the glomerular markers of kidney disease, estimated glomerular filtration rate (eGFR) and albuminuria, with frailty and cognition are well established. However, the relationship of kidney tubule injury and dysfunction with frailty and cognition is unknown. STUDY DESIGN: Observational cross-sectional study. SETTING & PARTICIPANTS: 2,253 participants with eGFR<60mL/min/1.73m2 in the Systolic Blood Pressure Intervention Trial (SPRINT). EXPOSURE: Eight urine biomarkers: interleukin 18 (IL-18), kidney injury molecule 1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), chitinase-3-like protein 1 (YKL-40), monocyte chemoattractant protein 1 (MCP-1), α1-microglobulin (A1M), ß2-microglobulin (B2M), and uromodulin (Umod). OUTCOME: Frailty was measured using a previously validated frailty index (FI), categorized as fit (FI≤0.10), less fit (0.100.21). Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA). ANALYTICAL APPROACH: Associations between kidney tubule biomarkers with categorical FI were evaluated using multinomial logistic regression with the fit group as the reference. Cognitive function was evaluated using linear regression. Models were adjusted for demographic, behavioral, and clinical variables including eGFR and urine albumin. RESULTS: Three of the 8 urine biomarkers of tubule injury and dysfunction were independently associated with FI. Each 2-fold higher level of urine KIM-1, a marker of tubule injury, was associated with a 1.22 (95% CI, 1.01-1.49) greater odds of being in the frail group. MCP-1, a marker of tubulointerstitial fibrosis, was associated with a 1.30 (95% CI, 1.04-1.64) greater odds of being in the frail group, and A1M, a marker of tubule reabsorptive capacity, was associated with a 1.48 (95% CI, 1.11-1.96) greater odds of being in the frail group. These associations were independent of confounders including eGFR and urine albumin, and were stronger than those of urine albumin with FI (1.15 [95% CI, 0.99-1.34]). Higher urine B2M, another marker of tubule reabsorptive capacity, was associated with worse cognitive scores at baseline (ß: -0.09 [95% CI, -0.17 to-0.01]). Urine albumin was not associated with cognitive function. LIMITATIONS: Cross-sectional design, and FI may not be generalizable in other populations. CONCLUSIONS: Urine biomarkers of tubule injury, fibrosis, and proximal tubule reabsorptive capacity are variably associated with FI and worse cognition, independent of glomerular markers of kidney health. Future studies are needed to validate these results among other patient populations.

Asunto(s)

Presión Sanguínea/fisiología , Cognición/fisiología , Fragilidad/orina , Túbulos Renales/lesiones , Túbulos Renales/metabolismo , Insuficiencia Renal Crónica/orina , Anciano , Anciano de 80 o más Años , Biomarcadores/orina , Quimiocina CCL2/orina , Estudios Transversales , Femenino , Fragilidad/diagnóstico , Fragilidad/epidemiología , Tasa de Filtración Glomerular/fisiología , Receptor Celular 1 del Virus de la Hepatitis A/metabolismo , Humanos , Túbulos Renales/patología , Masculino , Persona de Mediana Edad , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/epidemiología

RESUMEN

Excessive consumption of fructose (FR) leads to obesity, metabolic syndrome (MS) and insulin resistance, which are known risk factors for kidney stones. The epidemiological study has suggested the association between fructose consumption and urolithiasis, but the precise mechanism is still not well understood. Male Wistar rats were assigned for 8 weeks to three groups with different FR content in diet: RD (n = 5)-regular diet with a FR < 3%; F10 (n = 6)-regular diet with an addition of 10% Fr in drinking water; F60 (n = 5)-60% FR as a solid food. Serum concentration of FR, creatinine (Cr), insulin (Ins), triglycerides (Tg), homocysteine (HCS), uric acid (UA), calcium (Ca), phosphate (Pi), magnesium (Mg) and sodium (Na) were measured. Based on 24 h urine collection the following tests were performed: urine pH, proteinuria (PCR), excretion of N-Acetyl-(D)-Glucosaminidase (NAG), monocyte chemoattractant protein (MCP-1), uric acid (uUAEx), phosphate (uPiEx), calcium (uCaEx), magnesium (uMgEx) and sodium (uNaEx). The creatinine clearance (CrCl) was calculated. Calcium deposits in kidney sections were examined using hematoxylin and eosin (HE) and von Kossa stains. The rats on F10 and F60, as compared to the RD diet, showed a tendency for lower CrCl, higher HCS level and some features of MS as higher Ins and TG levels. Interestingly, F10 (fluid) versus F60 (solid) diet led to higher serum Ins levels. F10 and F60 versus RD demonstrated higher urinary excretion of MCP-1 and NAG which were suggestive for inflammatory injury of the proximal tubule. F10 and F60 as compared to RD showed significantly lower uUAEx, although there were no differences in clearance and fractional excretion of UA. F60 versus RD induced severe phosphaturia (>30×) and natriuria (4×) and mild calciuria. F10 versus RD induced calciuria (3×), phosphaturia (2×) and mild natriuria. Calcium phosphate stones within the tubules and interstitium were found only in rats on FR diet, respectively, in two rats from the F10 group and another two in the F60 group. The rats which developed stones were characterized by significantly higher serum insulin concentration and urinary excretion of calcium and magnesium. A fructose-rich diet may promote development of calcium stones due to proximal tubule injury and metabolic syndrome.

Asunto(s)

Dieta , Túbulos Renales/lesiones , Síndrome Metabólico/etiología , Urolitiasis/etiología , Animales , Ingestión de Alimentos , Electrólitos/orina , Fructosa , Túbulos Renales/patología , Masculino , Síndrome Metabólico/sangre , Síndrome Metabólico/orina , Estado Nutricional , Ratas Wistar , Factores de Riesgo , Urinálisis , Urolitiasis/sangre , Urolitiasis/orina

RESUMEN

Renal ischemia reperfusion injury (IRI) is associated with inflammation, including neutrophil infiltration that exacerbates the initial ischemic insult. The molecular pathways involved are poorly characterized and there is currently no treatment. We performed an in silico analysis demonstrating changes in NFκB-mediated gene expression in early renal IRI. We then evaluated NFκB-blockade with a BRD4 inhibitor on neutrophil adhesion to endothelial cells in vitro, and tested BRD4 inhibition in an in vivo IRI model. BRD4 inhibition attenuated neutrophil adhesion to activated endothelial cells. In vivo, IRI led to increased expression of cytokines and adhesion molecules at 6 h post-IRI with sustained up-regulated expression to 48 h post-IRI. These effects were attenuated, in part, with BRD4 inhibition. Absolute neutrophil counts increased significantly in the bone marrow, blood, and kidney 24 h post-IRI. Activated neutrophils increased in the blood and kidney at 6 h post-IRI and remained elevated in the kidney until 48 h post-IRI. BRD4 inhibition reduced both total and activated neutrophil counts in the kidney. IRI-induced tubular injury correlated with neutrophil accumulation and was reduced by BRD4 inhibition. In summary, BRD4 inhibition has important systemic and renal effects on neutrophils, and these effects are associated with reduced renal injury.

Asunto(s)

Adhesión Celular/efectos de los fármacos , Proteínas de Ciclo Celular/antagonistas & inhibidores , Células Endoteliales/metabolismo , Endotelio Vascular/metabolismo , Activación Neutrófila/efectos de los fármacos , Neutrófilos/inmunología , Proteínas Nucleares/antagonistas & inhibidores , Daño por Reperfusión/metabolismo , Factores de Transcripción/antagonistas & inhibidores , Animales , Proteínas de Ciclo Celular/metabolismo , Línea Celular Transformada , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Humanos , Riñón/citología , Riñón/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Neutrófilos/efectos de los fármacos , Proteínas Nucleares/metabolismo , Daño por Reperfusión/inmunología , Transducción de Señal/efectos de los fármacos , Factores de Transcripción/metabolismo

RESUMEN

Objective: To investigate the protective effect of somatostatin (SS) on acute kidney injury (AKI) of paraquat (PQ) poisoned mice and its mechanism. Methods: From December 2017 to April 2018, a total of 48 SPF male BALB/C mice were selected and randomly divided into 4 groups, with 12 mice in each group: Control group, SS group (20 mg/kg SS was injected 1 hour before and 3 hours after gavage with normal saline) , PQ group (2% PQ 60 mg/kg by gavage) and PQ+SS group (Intragastric administration was performed with 2% PQ solution of 60 mg/kg, and 20 mg/kg SS was administered 1 h before and 3 h after intragastric administration) , 12 mice in each group were observed for the general situation and behavioral effects. After 24 hours of modeling, mice were sacrificed.Then blood was extracted after eyeball was removed, and both kidneys were removed by laparotomy. Serum IL-6, TNF-α and MPO levels were determined by ELISA. The characteristic pathological changes of toxic renal tubular injury were observed under light microscope and scored accordingly. The changes of NF-κB expression were detected by Western-Blot, SOD, Caspase-3 and malondialdehyde (MDA) were detected by chemical colorimetry. Results: Mice in Control group and SS group showed normal general conditions and behaviors; Mice in PQ group were significantly worse than those in Control group, showing decreased feeding and activity, dry fur, hair shedding and listless spirit; The above symptoms in the mice of PQ+SS group were alleviated compared with the PQ group. Under the light microscope, the renal tissue structure of PQ group was obviously disordered and severely damaged, and the nephropathy score was (6.14±0.72) . The performance of PQ+SS group under light microscope was improved compared with PQ group, and nephropathy score (4.36±0.42) decreased (P<0.05) . Compared with the Control group, serum TNF-α (39.89±3.32) pg/ml, IL-6 (77.29±4.77) pg/ml, renal NF-κB (2.29±0.097) , MPO (0.31±0.017) µg/ml, MDA (0.91±0.03) mmol/mg prot, and Caspase-3 (376.51±8.24) % levels were significantly increased in the PQ group, while the level of renal SOD (2.36±0.73) U/mg prot was significantly decreased (P<0.05) . Compared with the PQ group, serum TNF-α (33.82±1.57) pg/ml, IL-6 (58.49±5.89) pg/ml, renal NF-κB (0.84±0.05) , MPO (0.22±0.01) µg/ml, MDA (0.72±0.05) mmol/mg prot, Caspase-3 (327.32±21.93) % decreased significantly, and renal SOD (4.90±0.81) U/mg prot increased significantly in the PQ+SS group (P<0.05) . Conclusion: PQ poisoning can lead to AKI in mice, while SS can reduce AKI caused by PQ poisoning, improve the general survival state of PQ poisoned mice, and play a certain protective role in kidney injury caused by PQ poisoning, which may be achieved by inhibiting oxidative stress response, inflammatory response and apoptosis caused by poisoning.

Asunto(s)

Paraquat/toxicidad , Somatostatina/metabolismo , Animales , Riñón , Pulmón , Masculino , Ratones , Ratones Endogámicos BALB C

RESUMEN

BACKGROUND: Recent data have shown that severe acute respiratory syndrome coronavirus 2 can infect renal proximal tubular cells via Angiotensin Converting Enzyme 2 (ACE2) . Our objective was to determine whether Fanconi syndrome is a frequent clinical feature in coronavirus disease 2019 (COVID-19) patients. METHODS: A retrospective cohort of 42 laboratory-confirmed COVID-19 patients without history of kidney disease hospitalized in University Hospital of Nancy was investigated. Patients were admitted to the intensive care unit (ICU) (n = 28) or the Medical department (n = 14) and were screened at least once for four markers of proximal tubulopathy. RESULTS: The mean (standard deviation) follow-up was 19.7 (±12.2) days. Of the patients, 75% (30/40) showed at least two proximal tubule abnormalities (incomplete Fanconi syndrome). The main disorders were proteinuria (88%, n = 35), renal phosphate leak defined by renal phosphate threshold/glomerular filtration rate (TmPi/GFR) <0.77 (55%, n = 22), hyperuricosuria (43%, n = 17) and normoglycaemic glycosuria (30%, n = 12). At the time of the first renal evaluation, ICU patients presented more frequent (96 versus 62%, P = 0.0095) and more severe (844 ± 343 versus 350 ± 221 mg/g, P = 0.0001) proteinuria, and a trend for an increased number of proximal tubule abnormalities (P = 0.038). During follow-up, they presented a lower nadir of serum phosphate [median (interquartile range) 0.68 (0.43-0.76) versus 0.77 (0.66-1.07) mmol/L, P = 0.044] and Acute kidney Injury (AKI) during the hospitalization (P = 0.045). Fanconi syndrome preceded severe AKI KDIGO Stages 2 and 3 in 88% (7/8) of patients. Proximal tubular abnormalities (such as proteinuria, TmPi/GFR and glycosuria in five, two and two patients, respectively) were not detected anymore in recovering patients before hospital discharge. CONCLUSION: Incomplete Fanconi syndrome is highly frequent in COVID-19 patients and precedes AKI or disappears during the recovery phase.

RESUMEN

BACKGROUND AND OBJECTIVES: eGFR and albuminuria primarily reflect glomerular function and injury, whereas tubule cell atrophy and interstitial fibrosis on kidney biopsy are important risk markers for CKD progression. Kidney tubule injury markers have primarily been studied in hospitalized AKI. Here, we examined the association between urinary kidney tubule injury markers at baseline with subsequent loss of kidney function in persons with nondiabetic CKD who participated in the Systolic Blood Pressure Intervention Trial (SPRINT). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Among 2428 SPRINT participants with CKD (eGFR<60 ml/min per 1.73 m2) at baseline, we measured urine markers of tubule injury (IL-18, kidney injury molecule-1 [KIM-1], neutrophil gelatinase-associated lipocalin [NGAL]), inflammation (monocyte chemoattractant protein-1 [MCP-1]), and repair (human cartilage glycoprotein-40 [YKL-40]). Cox proportional hazards models evaluated associations of these markers with the kidney composite outcome of 50% eGFR decline or ESKD requiring dialysis or kidney transplantation, and linear mixed models evaluated annualized change in eGFR. RESULTS: Mean participant age was 73±9 (SD) years, 60% were men, 66% were white, and mean baseline eGFR was 46±11 ml/min per 1.73 m2. There were 87 kidney composite outcome events during a median follow-up of 3.8 years. Relative to the respective lowest quartiles, the highest quartiles of urinary KIM-1 (hazard ratio, 2.84; 95% confidence interval [95% CI], 1.31 to 6.17), MCP-1 (hazard ratio, 2.43; 95% CI, 1.13 to 5.23), and YKL-40 (hazard ratio, 1.95; 95% CI, 1.08 to 3.51) were associated with higher risk of the kidney composite outcome in fully adjusted models including baseline eGFR and urine albumin. In linear analysis, urinary IL-18 was the only marker associated with eGFR decline (-0.91 ml/min per 1.73 m2 per year for highest versus lowest quartile; 95% CI, -1.44 to -0.38), a finding that was stronger in the standard arm of SPRINT. CONCLUSIONS: Urine markers of tubule cell injury provide information about risk of subsequent loss of kidney function, beyond the eGFR and urine albumin.

Asunto(s)

Albuminuria/orina , Quimiocina CCL2/orina , Proteína 1 Similar a Quitinasa-3/orina , Tasa de Filtración Glomerular , Receptor Celular 1 del Virus de la Hepatitis A/metabolismo , Interleucina-18/orina , Túbulos Renales/metabolismo , Insuficiencia Renal Crónica/orina , Anciano , Anciano de 80 o más Años , Albuminuria/diagnóstico , Albuminuria/etiología , Albuminuria/fisiopatología , Biomarcadores/orina , Progresión de la Enfermedad , Femenino , Humanos , Hipertensión/complicaciones , Túbulos Renales/patología , Túbulos Renales/fisiopatología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Ensayos Clínicos Controlados Aleatorios como Asunto , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/fisiopatología , Medición de Riesgo , Factores de Riesgo , Urinálisis

RESUMEN

Renal interstitial fibrosis (RIF) often occurs in many chronic kidney diseases (CKD). Hirudin now is applied to treat fibrosis in some organs. In this study, we verified the treatment effects of hirudin on RIF in vivo and in vitro with the underlying mechanism. The RIF in vivo was the unilateral ureteral obstruction (UUO) model and RIF in vitro was the renal tubular epithelial cells induced by TGF-ß. The renal pathological changes and renal fibrosis were observed by hematoxylin and eosin (H&E) staining and Masson staining. The α-SMA in renal tissues was detected by immunohistochemistry. The inflammatory factors were analyzed by the ELISA assay. The cell apoptosis was observed by TUNEL assay. The related proteins of fibrosis, epithelial-mesenchymal transition (EMT) and apoptosis were assessed by western blot analysis. The experimental data demonstrated that hirudin decreased fibrosis, EMT, inflammation and cell apoptosis in renal tissues of UUO rats and TGF-ß-induced renal tubular epithelial cells. Furthermore, hirudin also reduced the expression of collgen-I, FN, α-SMA, N-cad, slug, E-cad, IL-1ß, IL-6 and TNF-α in mice serum and TGF-ß-induced renal tubular epithelial cells. The apoptosis related proteins (pro-caspase3, pro-caspase9, bcl2 and bax) expression was also down-regulated in renal tissues of UUO rats. In conclusion, hirudin depressed the fibrosis in renal tissues and renal tubular epithelial cells by inhibiting the inflammation, regulating the related proteins of fibrosis and ETM and decreasing the apoptosis of renal tubular epithelial cells. These findings may offer an effective treatment method for RIF.

Asunto(s)

Antiinflamatorios/administración & dosificación , Terapia con Hirudina , Hirudinas/administración & dosificación , Inflamación/tratamiento farmacológico , Túbulos Renales/patología , Insuficiencia Renal Crónica/tratamiento farmacológico , Obstrucción Ureteral/tratamiento farmacológico , Animales , Apoptosis , Células Cultivadas , Modelos Animales de Enfermedad , Fibrosis , Humanos , Masculino , Medicina Tradicional China , Ratones , Ratones Endogámicos BALB C , Ratas

RESUMEN

Acute kidney injury (AKI) is an acute and critical kidney disease that seriously threatens human health and even life. It can lead to the chronic kidney disease (CKD) and end-stage kidney disease (ESRD), causing global public health problems. At present, the transition mechanism from AKI to CKD has not been fully elucidated, and renal tubular injury may play an important role in it. This paper reviews the role of renal tubular injury in the transition from AKI to CKD including cell dedifferentiation, inflammatory cell infiltration, hypoxia and vascular density decline, mitochondrial dysfunction and oxidative stress, G2/M cell cycle arrest, autophagy, TGFβ signaling pathway and Wnt signaling pathway.