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Type 2 diabetes mellitus (T2DM) is a widespread chronic disease characterized by persistent hyperglycemia, leading to severe complications such as diabetic cardiomyopathy and nephropathy, significantly affecting patient health and quality of life. The complex mechanisms underlying these complications include chronic inflammation, oxidative stress, and metabolic dysregulation. Diabetic cardiomyopathy, marked by structural and functional heart abnormalities, and diabetic nephropathy, characterized by progressive kidney damage, are major contributors to the increased morbidity and mortality associated with T2DM. AdipoRon, a synthetic adiponectin receptor agonist, has shown potential in preclinical studies for mimicking the beneficial effects of endogenous adiponectin, reducing inflammation and oxidative stress, and improving lipid metabolism and mitochondrial function. This systematic review evaluates the therapeutic potential of AdipoRon, focusing on its impact on diabetic cardiomyopathy and nephropathy. Through a comprehensive literature search and analysis, we highlight AdipoRon's role in ameliorating cardiovascular and renal complications in various animal models and cellular systems. The findings underscore the urgent need for translational clinical studies to validate AdipoRon's efficacy and safety in human populations, aiming to advance this promising therapeutic approach from experimental models to clinical application, potentially offering new hope for improved management of diabetic complications.
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Diabetes mellitus and its complications are a known public health problem nowadays. Diabetic nephropathy is one of the main complications and the result of multiple mechanisms, including: activation of the renin-angiotensin-aldosterone system, formation of advanced glycation end products and chronic inflammation that led to glomerular and tubulo-interstitial damage producing mesangial expansion and glomerulosclerosis, which finally results in chronic kidney disease. Early detection of diabetic nephropathy is essential for adequate intervention to stop, or at least slow down its progression. Multiple markers have been described, not only the classic ones such as serum creatinine, urea, and albuminuria, but at this point also novel biomarkers such as neutrophil gelatinase-associated lipocalin, tumor necrosis factor 1 receptor and monocyte chemoattractant protein-1, among others. The aim of this article was to provide an update review of the role of biomarkers in the diagnosis of diabetic nephropathy.
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BACKGROUND: MiRNA-146a and miRNA-223 are key epigenetic regulators of toll-like receptor 4 (TLR4)/tumor necrosis factor-receptor-associated factor 6 (TRAF6)/NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome pathway, which is involved in diabetic nephropathy (DN) pathogenesis. The currently available oral anti-diabetic treatments have been insufficient to halt DN development and progression. Therefore, this work aimed to assess the renoprotective effect of the natural compound 6-gingerol (GR) either alone or in combination with metformin (MET) in high-fat diet/streptozotocin-induced DN in rats. The proposed molecular mechanisms were also investigated. METHODS: Oral gavage of 6-gingerol (100 mg/kg) and metformin (300 mg/kg) were administered to rats daily for eight weeks. MiRNA-146a, miRNA-223, TLR4, TRAF6, nuclear factor-kappa B (NF-κB) (p65), NLRP3, caspase-1, and hypoxia-inducible factor-1 alpha (HIF-1α) mRNA expressions were measured using real-time PCR. ELISA was used to measure TLR4, TRAF6, NLRP3, caspase-1, tumor necrosis factor-alpha (TNF-α), and interleukin-1-beta (IL-1ß) renal tissue levels. Renal tissue histopathology and immunohistochemical examination of fibronectin and NF-κB (p65) were performed. RESULTS: 6-Gingerol treatment significantly reduced kidney tissue damage and fibrosis. 6-Gingerol up-regulated miRNA-146a and miRNA-223 and reduced TLR4, TRAF6, NF-κB (p65), NLRP3, caspase-1, TNF-α, IL-1ß, HIF-1α and fibronectin renal expressions. 6-Gingerol improved lipid profile and renal functions, attenuated renal hypertrophy, increased reduced glutathione, and decreased blood glucose and malondialdehyde levels. 6-Gingerol and metformin combination showed superior renoprotective effects than either alone. CONCLUSION: 6-Gingerol demonstrated a key protective role in DN by induction of miRNA-146a and miRNA-223 expression and inhibition of TLR4/TRAF6/NLRP3 inflammasome signaling. 6-Gingerol, a safe, affordable, and abundant natural compound, holds promise for use as an adjuvant therapy with metformin in diabetic patients to attenuate renal damage and stop the progression of DN.
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Catecóis , Diabetes Mellitus Experimental , Nefropatias Diabéticas , Dieta Hiperlipídica , Inflamassomos , Metformina , MicroRNAs , Animais , Masculino , Ratos , Catecóis/farmacologia , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Quimioterapia Combinada , Álcoois Graxos/farmacologia , Hipoglicemiantes/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Metformina/farmacologia , Metformina/administração & dosagem , MicroRNAs/metabolismo , MicroRNAs/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Estreptozocina , Receptor 4 Toll-Like/metabolismoRESUMO
Type 1 Diabetes Mellitus (T1DM) can generate severe complications, such as Diabetic Kidney Disease (DKD) or Diabetic Nephropathy (DN), with it emerging as the leading cause of terminal (end-stage) renal disease all over the world. For T1DM, the clinical evaluation of DKD uses markers like the Glomerular Filtration Rate (GFR) and the Urinary Albumin Excretion (UAE). However, early diagnosis of DKD is still a challenge. For this reason, investigating molecular markers, such as microRNAs (miRNAs), offers a promising perspective to an early diagnosis, highlighting the stability and the ability to reflect incipient molecular manifestations. Thus, here we investigated four miRNAs (hsa-let-7i-5p, hsa-miR-143-3p, hsa-miR-501-3p, and hsa-miR-100-5p) regarding nephropathy in patients with T1DM, considering the albuminuria (micro and macro) as a standard to evaluate the groups. As a result, we found a reduced expression of miR-100-5p in patients with MIC, indicating a protective role in nephropathy. Beyond that, expression levels between the groups (Non vs. UAE) were not significant when comparing the miRNAs miR-501-3p and miR-143-3p. Finally, miR-143-3p and miR-100-5p were linked to some target genes such as AKT1, MMP13, and IGF1R, that are connected to signal pathways and cellular metabolism.
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Biomarcadores , Diabetes Mellitus Tipo 1 , Nefropatias Diabéticas , MicroRNAs , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Albuminúria/genética , Biomarcadores/análise , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/complicações , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Regulação para Baixo/genética , Taxa de Filtração Glomerular , MicroRNAs/genética , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismoRESUMO
Induction of the adenosine receptor A2B (A2BAR) expression in diabetic glomeruli correlates with an increased abundance of its endogenous ligand adenosine and the progression of kidney dysfunction. Remarkably, A2BAR antagonism protects from proteinuria in experimental diabetic nephropathy. We found that A2BAR antagonism preserves the arrangement of podocytes on the glomerular filtration barrier, reduces diabetes-induced focal adhesion kinase (FAK) activation, and attenuates podocyte foot processes effacement. In spreading assays using human podocytes in vitro, adenosine enhanced the rate of cell body expansion on laminin-coated glass and promoted peripheral pY397-FAK subcellular distribution, while selective A2BAR antagonism impeded these effects and attenuated the migratory capability of podocytes. Increased phosphorylation of the Myosin2A light chain accompanied the effects of adenosine. Furthermore, when the A2BAR was stimulated, the cells expanded more broadly and more staining of pS19 myosin was detected which co-localized with actin cables, suggesting increased contractility potential in cells planted onto a matrix with a stiffness similar to of the glomerular basement membrane. We conclude that A2BAR is involved in adhesion dynamics and contractile actin bundle formation, leading to podocyte foot processes effacement. The antagonism of this receptor may be an alternative to the intervention of glomerular barrier deterioration and proteinuria in the diabetic kidney disease.
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Adesão Celular , Diabetes Mellitus Experimental , Proteína-Tirosina Quinases de Adesão Focal , Podócitos , Proteinúria , Receptor A2B de Adenosina , Animais , Humanos , Masculino , Ratos , Adenosina/metabolismo , Adenosina/farmacologia , Antagonistas do Receptor A2 de Adenosina/farmacologia , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/tratamento farmacológico , Proteína-Tirosina Quinases de Adesão Focal/efeitos dos fármacos , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Cadeias Leves de Miosina/metabolismo , Fosforilação/efeitos dos fármacos , Podócitos/metabolismo , Podócitos/efeitos dos fármacos , Podócitos/patologia , Proteinúria/metabolismo , Receptor A2B de Adenosina/efeitos dos fármacos , Receptor A2B de Adenosina/metabolismoRESUMO
Circular RNAs (circRNAs) are noncoding singlestranded covalently closed RNA molecules that are considered important as regulators of gene expression at the transcriptional and posttranscriptional levels. These molecules have been implicated in the initiation and progression of multiple human diseases, ranging from cancer to inflammatory and metabolic diseases, including diabetes mellitus and its vascular complications. The present article aimed to review the current knowledge on the biogenesis and functions of circRNAs, as well as their role in cell processes associated with diabetic nephropathy. In addition, novel potential interactions between circRNAs expressed in renal cells exposed to highglucose concentrations and the transcription factors cJun and cFos are reported.
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Diabetes Mellitus , Nefropatias Diabéticas , Neoplasias , Humanos , RNA Circular/genética , RNA Circular/metabolismo , Nefropatias Diabéticas/genética , RNA/genética , Neoplasias/genética , Regulação da Expressão GênicaRESUMO
BACKGROUND: To evaluate structural changes in retina and choroid in patients with type 2 diabetes (T2D) and their association with diabetic kidney disease (DKD). METHODS: T2D patients with mild or no diabetic retinopathy (DR) were followed for 3 years using structural SS-OCT and OCT angiography (OCT-A) taken every 6 months. Parameters were compared longitudinally and according to the DKD status on baseline. RESULTS: One hundred and sixty eyes from 80 patients were followed for 3 years, 72 with no DKD (nDKD) at baseline and 88 with DKD. Trend analysis of T2D showed significant thinning in GCL + and circumpapillary retinal fiber neural layer (cRFNL), choroid, and decreased vascular density (VD) in superficial plexus and central choriocapillaris with foveal avascular zone (FAZ) enlargement. Patients with no DKD on baseline presented more significant declines in retinal center and choroidal thickness, increased FAZ and loss of nasal and temporal choriocapillaris volume. In addition, the nDKD group had worse glycemic control and renal parameters at the end of the study. CONCLUSION: Our data suggests the potential existence of early and progressive neurovascular damage in the retina and choroid of patients with Type 2 Diabetes (T2D) who have either no or mild Diabetic Retinopathy (DR). The progression of neurovascular damage appears to be correlated with parameters related to glycemic control and renal damage.
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Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Retinopatia Diabética , Humanos , Diabetes Mellitus Tipo 2/complicações , Estudos Prospectivos , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/complicações , Tomografia de Coerência Óptica , Vasos Retinianos/diagnóstico por imagem , Angiofluoresceinografia , Retina , Retinopatia Diabética/complicações , Retinopatia Diabética/diagnóstico , Corioide/irrigação sanguíneaRESUMO
SUMMARY: This study assessed the effects of Acacia Senegal (AS) combined with insulin on Na+/K+-ATPase (NKA) activity and mRNA expression, serum glucose, renal function, and oxidative stress in a rat model of diabetic nephropathy (DN). Sixty rats were equally divided into six groups: normal control, normal+AS, diabetic (DM), DM+insulin, DM+AS, and DM+insulin+AS groups. Diabetes mellitus (type 1) was induced by a single injection of streptozotocin (65 mg/kg), and insulin and AS treatments were carried until rats were culled at the end of week 12. Serum glucose and creatinine levels, hemoglobin A1c (HbA1c) were measured. Renal homogenate levels of NKA activity and gene expression, malondialdehyde, superoxide dismutase (SOD), catalase and reduced glutathione (GSH) were evaluated as well as kidney tissue histology and ultrastructure. Diabetes caused glomerular damage and modulation of blood and tissue levels of creatinine, glucose, HbA1c, malondialdehyde, NKA activity and gene expression, SOD, catalase and GSH, which were significantly (p<0.05) treated with AS, insulin, and insulin plus AS. However, AS+insulin treatments were more effective. In conclusion, combined administration of AS with insulin to rats with DN decreased NKA activity and gene expression as well as oxidative stress, and improved glycemic state and renal structure and function.
Este estudio evaluó los efectos de Acacia senegal (AS) combinada con insulina sobre la actividad Na+/K+- ATPasa (NKA) y la expresión de ARNm, la glucosa sérica, la función renal y el estrés oxidativo en un modelo de nefropatía diabética (ND) en ratas. Sesenta ratas se dividieron equitativamente en seis grupos: control normal, normal+AS, diabética (DM), DM+insulina, DM+AS y DM+insulina+AS. La diabetes mellitus (tipo 1) se indujo mediante una única inyección de estreptozotocina (65 mg/kg), y los tratamientos con insulina y AS se llevaron a cabo hasta que las ratas fueron sacrificadas al final de la semana 12. Se midieron niveles séricos de glucosa y creatinina, hemoglobina A1c (HbA1c). Se evaluaron los niveles de homogeneizado renal de actividad NKA y expresión génica, malondialdehído, superóxido dismutasa (SOD), catalasa y glutatión reducido (GSH), así como la histología y ultraestructura del tejido renal. La diabetes causó daño glomerular y modulación de los niveles sanguíneos y tisulares de creatinina, glucosa, HbA1c, malondialdehído, actividad y expresión génica de NKA, SOD, catalasa y GSH, los cuales fueron tratados significativamente (p<0,05) con AS, insulina e insulina más AS. Sin embargo, los tratamientos con AS+insulina fueron más efectivos. En conclusión, la administración combinada de AS con insulina a ratas con DN disminuyó la actividad de NKA y la expresión genética, así como el estrés oxidativo, y mejoró el estado glucémico y la estructura y función renal.
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Animais , Masculino , Ratos , Extratos Vegetais/administração & dosagem , ATPase Trocadora de Sódio-Potássio/efeitos dos fármacos , Nefropatias Diabéticas/tratamento farmacológico , Acacia/química , Superóxido Dismutase , Hemoglobinas Glicadas/análise , Extratos Vegetais/farmacologia , Expressão Gênica , Ratos Sprague-Dawley , ATPase Trocadora de Sódio-Potássio/genética , Estresse Oxidativo , Microscopia Eletrônica de Transmissão , Modelos Animais de Doenças , Quimioterapia Combinada , Controle Glicêmico , Insulina/administração & dosagem , Rim/efeitos dos fármacos , MalondialdeídoRESUMO
Objective: the present study aimed to evaluate the prevalence of diabetic nephropathy and diabetic retinopathy, in addition to the associations that can be established between these microvascular complications of diabetes mellitus. Methods: this was a retrospective study, a systematic review without metaanalysis. The authors used the Pubmed and SciELO databases to search the terms "diabetic nephropathy", "diabetic retinopathy" and "type 2 diabetes", including publications dated 2011 to 2021. Results/Discussion: the results presented were a synthesis of patients with both pathologies and their correlations, in addition to associated laboratory changes and agreement between the stages or severity of both conditions. Conclusions: DN and DR are pathologies that are directly interconnected and cause repercussions for patients.
Objetivo: o presente estudo teve como objetivo avaliar a prevalência de nefropatia diabética e retinopatia diabética, além das associações que podem ser estabelecidas entre essas complicações microvasculares do diabetes mellitus. Métodos: estudo retrospectivo, revisão sistemática sem metanálise, os autores utilizaram as bases de dados Pubmed e SciELO para busca dos termos "nefropatia diabética", "retinopatia diabética" e "diabetes tipo 2", incluindo publicações datadas de 2011 a 2021. Resultados/Discussão: os resultados apresentados foram uma síntese dos pacientes com ambas as patologias e suas correlações, além de alterações laboratoriais associadas e concordância entre os estágios ou gravidade de ambas as condições. Conclusões: ND e RD são patologias que estão diretamente interligadas e causam repercussões aos pacientes.
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Diabetes Mellitus , Retinopatia Diabética , Insuficiência Renal CrônicaRESUMO
OBJECTIVE: This review aimed to assess the utility of urinary N-acetyl-ß-D-glucosaminidase (uNAG) as a prognostic biomarker for nephropathy in patients with type 2 diabetes mellitus. METHODS: The search for relevant studies was conducted across multiple databases, including PubMed (Medline), EMBASE, LILACS, CENTRAL, IBECS, and gray literature. We employed a random effects model to calculate the standardized mean difference and 95% confidence interval. Furthermore, we assessed heterogeneity using Cochrane's Q test and Higgins' I2 statistics. RESULTS: This review included a total of 16 articles involving 1669 patients, with 13 being case-control studies and three being cohorts. The meta-analysis conducted across all studies revealed significant heterogeneity. However, subgroup analysis of four studies indicated that an increase in uNAG among normoalbuminuric patients was associated with the development of macroalbuminuria (DMP = - 1.47; 95% CI = - 1.98 to 0.95; p < 0.00001; I2 = 45%). Conversely, it did not demonstrate effectiveness in predicting the development of microalbuminuria (DMP = 0.26; 95% CI = - 0.08 to 0.60; p = 0.13; I2 = 17%). CONCLUSIONS: Elevated uNAG levels in normoalbuminuric patients may indicate an increased risk for the development of macroalbuminuria, but not microalbuminuria. However, the high heterogeneity observed among the studies highlights the necessity for further research to validate these findings.
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Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Humanos , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/complicações , Diabetes Mellitus Tipo 2/complicações , Acetilglucosaminidase , Prognóstico , Biomarcadores , Albuminúria/complicaçõesRESUMO
The objective of this study was to assess the value of the abnormal circadian blood pressure pattern by ambulatory blood pressure monitoring (ABPM) to predict the onset of abnormal albuminuria in normotensive and normoalbuminuric DM1 patients. The participators were submitted to ABPM and followed prospectively until the onset of albuminuria or the end of follow-up. The patients with normal circadian blood pressure pattern were compared with the non-dippers in regard of the time interval free of albuminuria. The survival curves were evaluated by the Kaplan-Meier method. Of 34 patients screened, 10 patients matched the exclusion criteria. Therefore, 24 patients were submitted to ABPM, aged 24 ± 8.3 y, 18 men, and all Caucasian. Elevated levels of albuminuria did not occurin any individual with normal systolic blood pressure dip (>10%) at 54 months of follow-up. Only 22% of patients among non-dippers were free of albuminuria (<30 mg/g maintained for 3 months) at the same time (p = 0.049). Patients that reached the outcome were homogeneous in regard to other clinical and ABPM data evaluated. Abnormal systolic blood pressure circadian pattern predicts the evolution to incipient nephropathy in normotensive normoalbuminuric DM1 patients.
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Diabetes Mellitus Tipo 1 , Hipertensão , Nefropatias , Masculino , Humanos , Pressão Sanguínea/fisiologia , Albuminúria , Monitorização Ambulatorial da Pressão Arterial , Ritmo Circadiano/fisiologiaRESUMO
The chronic complications of diabetes mellitus constitute a major public health problem. For example, diabetic eye diseases are the most important cause of blindness, and diabetic nephropathy is the most frequent cause of chronic kidney disease worldwide. The cellular and molecular mechanisms of these chronic complications are still poorly understood, preventing the development of effective treatment strategies. Tight junctions (TJs) are epithelial intercellular junctions located at the most apical region of cell-cell contacts, and their main function is to restrict the passage of molecules through the paracellular space. The TJs consist of over 40 proteins, and the most important are occludin, claudins and the zonula occludens. Accumulating evidence suggests that TJ disruption in different organs, such as the brain, nerves, retina and kidneys, plays a fundamental pathophysiological role in the development of chronic complications. Increased permeability of the blood-brain barrier and the blood-retinal barrier has been demonstrated in diabetic neuropathy, brain injury and diabetic retinopathy. The consequences of TJ disruption on kidney function or progression of kidney disease are currently unknown. In the present review, we highlighted the molecular events that lead to barrier dysfunction in diabetes. Further investigation of the mechanisms underlying TJ disruption is expected to provide new insights into therapeutic approaches to ameliorate the chronic complications of diabetes mellitus.
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Some chemoattractants and leukocytes such as M1 and M2 macrophages are known to be involved in the development of glomerulosclerosis during diabetic nephropathy (DN). In the course of diabetes, an altered and defective cellular metabolism leads to the increase in adenosine levels, and thus to changes in the polarity (M1/M2) of macrophages. MRS1754, a selective antagonist of the A2B adenosine receptor (A2BAR), attenuated glomerulosclerosis and decreased macrophage-myofibroblast transition in DN rats. Therefore, we aimed to investigate the effect of MRS1754 on the glomerular expression/secretion of chemoattractants, the intraglomerular infiltration of leukocytes, and macrophage polarity in DN rats. Kidneys/glomeruli of non-diabetic, DN, and MRS1754-treated DN rats were processed for transcriptomic analysis, immunohistopathology, ELISA, and in vitro macrophage migration assays. The transcriptomic analysis identified an upregulation of transcripts and pathways related to the immune system in the glomeruli of DN rats, which was attenuated using MRS1754. The antagonism of the A2BAR decreased glomerular expression/secretion of chemoattractants (CCL2, CCL3, CCL6, and CCL21), the infiltration of macrophages, and their polarization to M2 in DN rats. The in vitro macrophages migration induced by conditioned-medium of DN glomeruli was significantly decreased using neutralizing antibodies against CCL2, CCL3, and CCL21. We concluded that the pharmacological blockade of the A2BAR decreases the transcriptional expression of genes/pathways related to the immune response, protein expression/secretion of chemoattractants, as well as the infiltration of macrophages and their polarization toward the M2 phenotype in the glomeruli of DN rats, suggesting a new mechanism implicated in the antifibrotic effect of MRS1754.
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Acetamidas , Antagonistas do Receptor A2 de Adenosina , Polaridade Celular , Fatores Quimiotáticos , Nefropatias Diabéticas , Glomérulos Renais , Macrófagos , Purinas , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/imunologia , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/metabolismo , Fatores Quimiotáticos/antagonistas & inibidores , Fatores Quimiotáticos/genética , Fatores Quimiotáticos/metabolismo , Polaridade Celular/efeitos dos fármacos , Polaridade Celular/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Antagonistas do Receptor A2 de Adenosina/farmacologia , Receptor A2B de Adenosina , Acetamidas/farmacologia , Purinas/farmacologia , Animais , Ratos , Movimento Celular/efeitos dos fármacos , Masculino , Ratos Sprague-Dawley , Transcrição Gênica/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos , Imunidade/efeitos dos fármacos , Imunidade/genéticaRESUMO
Objective: The incidence of diabetic nephropathy (DN) is gradually increasing worldwide. Podocyte injury, such as podocyte apoptosis and loss of the slit diaphragm (SD)-specific markers are early pathogenic features of DN. Materials and methods: The cultured mouse podocytes were separated into a high glucose-treated (HG, 30mM) group to mimic DN in vitro, a low glucose-treated (LG, 5mM) group as a control and HG+ angiotensin-(1-7)(Ang-(1-7)) and HG+Ang-(1-7) + D-Ala7-Ang-(1-7) (A779, Ang-(1-7)/Mas receptor antagonist) experimental groups. The Cell Counting Kit-8 (CCK-8) method and flow cytometry was used to detect podocyte activity and podocyte apoptosis respectively. The expression of angiotensin type 1 receptor (AT1R), Mas receptor (MasR) and podocyte-specific markers were examined by q-PCR and Western blot, respectively. Results: The results showed that the decrease in podocyte activity; the increase in podocyte apoptosis; the decreased mRNA and protein expression of nephrin, podocin, WT-1 and MasR; and the upregulated expression of AT1R induced by HG could be reversed by Ang-(1-7). However, these effects were blocked by A779. The possible mechanisms of the Ang-(1-7)-mediated effect depended on MasR. In addition, the protective effect of Ang-(1-7) on podocyte activity was dose-dependent and most obvious at 10 µM. A779 had the greatest antagonistic action against Ang-(1-7) at a concentration of 10 µM. Conclusion: This study reveals that binding of Ang-(1-7) to its specific receptor MasR may counteract the effects of Ang II mediated by AT1R to significantly attenuate podocyte injury induced by high glucose. Ang-(1-7)/MasR targeting in podocytes may be a therapeutic approach to attenuate renal injury in DN.
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Angiotensina II , Nefropatias Diabéticas , Podócitos , Animais , Camundongos , Angiotensina II/farmacologia , Glucose/farmacologia , Podócitos/metabolismo , Podócitos/patologiaRESUMO
ABSTRACT Background: In addition to diabetic nephropathies (DNP), prevalence of nondiabetic nephropathies (NDNP) is also known to be frequent in patients diagnosed with type 2 Diabetes mellitus (DM). Early diagnosis of these conditions is important for the treatment and prognosis of these patients. Aim: This study aimed to investigate the relationships between clinical and laboratory findings of type 2 diabetic patients' renal biopsies. Material and Methods: We retrospectively reviewed the medical records of 140 patients who had diagnosis of type 2 DM and underwent renal biopsy from July 2020- August 2022 at nephrology clinics of Hospital Umraniye. Renal biopsy results, presence of hypertension, diabetic retinopathy, hematuria, proteinuria; duration of the disease, biopsy indications, glycated hemoglobin (HbA1c), serum creatinine, blood urea nitrogen, albumin, and proteinuria levels in 24h urine were measured. The statistical significance level was determined as p<0,05. Results: NDNP were detected in 43,7% of the patients. Among these the most common diagnosis was interstitial nephritis (20%). The most common biopsy indication was found to be nephrotic range proteinuria (30,7%). The difference between the DNP and NDNP patients' renal biopsy indications was statistically significant (p<0,001). DNP patients had a higher retinopathy incidence (60%,11%, p<0,001). A statistically significant difference was detected between the disease duration of DNP and NDNP groups (11,23 +5,74 years, p:0,002). According to multivariate regression analysis DR and HbA1c value, more than 7% have 4, 482 and 4,591-fold increased the risk of DNP incidence (p=0,021, p:0,024). Conclusion: Early diagnosis of DNP and NDNP of diabetic patients by performing renal biopsies affects the treatment and prognosis of the patients. Therefore, when evaluating diabetic patients, its necessary not to overlook the findings suggestive of NDNP.
RESUMEN Antecedentes: Además de las nefropatías diabéticas (DNP), también se conoce la prevalencia frecuente de nefropatías no diabéticas (NDNP) en pacientes diagnosticados con Diabetes mellitus tipo 2 (DM). El diagnóstico precoz de estas condiciones es importante para el tratamiento y pronóstico de estos pacientes. Objetivo: Este estudio tuvo como objetivo investigar las relaciones entre los hallazgos clínicos y de laboratorio de las biopsias renales de pacientes diabéticos tipo 2. Material y Métodos: Revisamos retrospectivamente las historias clínicas de 140 pacientes que tenían diagnóstico de DM tipo 2, desde julio de 2020 hasta agosto de 2022, y se les realizó biopsia renal en las clínicas de nefrología del Hospital Umraniye. Se revisaron los resultados de biopsia renal, presencia de hipertensión arterial, retinopatía diabética, hematuria y proteinuria así como también la duración de la enfermedad, las indicaciones de la biopsia, la hemoglobina glucosilada (HbA1c), la creatinina sérica, el nitrógeno ureico en sangre, la albúmina y los niveles de proteinuria en orina de 24 h. El nivel de significación estadística se determinó como p<0,05. Resultados: se detectaron NDNP en el 43,7% de los pacientes. Entre estos, el diagnóstico más común fue la nefritis intersticial (20%). La indicación de biopsia más frecuente resultó ser la proteinuria en rango nefrótico (30,7%). La diferencia entre las indicaciones de biopsia renal de los pacientes DNP y NDNP fue estadísticamente significativa (p<0,001). Los pacientes con DNP tuvieron una mayor incidencia de retinopatía (60%, 11%, p<0,001). Se detectó una diferencia estadísticamente significativa entre la duración de la enfermedad de los grupos DNP y NDNP (11,23 +5,74 años, p:0,002). De acuerdo con el análisis de regresión multivariado, la presencia de DR y el valor de HbA1c en más del 7% tienen 4,482 y 4,591 veces mayor riesgo de incidencia de DNP (p = 0,021, p: 0,024). Conclusión: El diagnóstico precoz de DNP y NDNP de pacientes diabéticos mediante la realización de biopsias renales afecta el tratamiento y pronóstico de los pacientes. Por lo tanto, al evaluar pacientes diabéticos, es necesario no pasar por alto los hallazgos sugestivos de NDNP.
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We have studied the effects of naringin (NAR), a flavonoid from citric fruits, on morphology, ultrastructure and function of the kidney in streptozotocin (STZ)-induced diabetic rats. Two groups of animals were used: (1) control rats and (2) STZ rats (60 mg STZ/kg b.w.). At 3 days after induction, one group of STZ-treated rats received 40 mg NAR/kg b.w. daily. NAR blocked completely alterations in the biochemical renal markers in STZ rats except the increase in serum urea that was partially avoided by the flavonoid. NAR ameliorated the kidney morphological lesions from STZ rats. STZ treatment induced round and smaller mitochondria, which was avoided by NAR. Citrate synthase, isocitrate and malate dehydrogenases, enzyme activities of the Krebs cycle, were decreased in STZ rats. NAR abolished this decrease in the latter proteins. NAR also prevented a decrease in the ATP synthase activity of the mitochondria from renal cortex by about 49% in STZ rats, returning the enzyme activity to control values. The nephroprotection caused by NAR is mediated through counteraction of oxidative stress in mitochondria of proximal tubules. NAR might be a therapeutic strategy to reduce the complication of diabetic nephropathy in type 1 diabetic patients.
Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Flavanonas , Ratos , Animais , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Estresse Oxidativo , Flavanonas/farmacologia , Flavanonas/uso terapêutico , Flavanonas/metabolismo , Rim , Estreptozocina/farmacologia , Mitocôndrias/metabolismoRESUMO
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.
Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Animais , Camundongos , Caspases , Fibrose , Glucose , Inflamação , Interleucina-18 , NF-kappa B/metabolismo , Piroptose , RNA Interferente PequenoRESUMO
Diabetic nephropathy (DN) is the leading cause of end-stage renal failure worldwide. Hyperglycemia generates reactive oxygen species (ROS), contributing to diabetic complications, especially in DN. Sodium Tungstate (NaW) is an effective antidiabetic agent for short and long-term treatments of both type 1 and type 2 diabetes models. In this study, we evaluated the effect of NaW on ROS production in bovine neutrophils incubated with platelet-activating factor (PAF) and in HK-2 cells induced by high glucose or H2O2. In addition, we evaluated the effect on iNOS expression in the type 1 diabetic rat model induced with streptozotocin (STZ). NaW inhibited ROS production in PAF-induced bovine neutrophils, and human tubular cells (HK-2) were incubated in high glucose or H2O2. In addition, NaW inhibited iNOS expression in glomeruli and tubular cells in the type 1 diabetic rat. This study demonstrates a new role for NaW as an active antioxidant and its potential use in treating DN.
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The global prevalence of diabetes continues to increase partly due to rapid urbanization and an increase in the aging population. Consequently, this is associated with a parallel increase in the prevalence of diabetic vascular complications which significantly worsen the burden of diabetes. For these diabetic vascular complications, there is still an unmet need for safe and effective alternative/adjuvant therapeutic interventions. There is also an increasing urge for therapeutic options to come from natural products such as plants. Hyperglycemia-induced oxidative stress is central to the development of diabetes and diabetic complications. Furthermore, oxidative stress-induced inflammation and insulin resistance are central to endothelial damage and the progression of diabetic complications. Human and animal studies have shown that polyphenols could reduce oxidative stress, hyperglycemia, and prevent diabetic complications including diabetic retinopathy, diabetic nephropathy, and diabetic peripheral neuropathy. Part of the therapeutic effects of polyphenols is attributed to their modulatory effect on endogenous antioxidant systems. This review attempts to summarize the established effects of polyphenols on endogenous antioxidant systems from the literature. Moreover, potential therapeutic strategies for harnessing the potential benefits of polyphenols for diabetic vascular complications are also discussed.
RESUMO
A Doença Renal do Diabetes (DRD) é assintomática nos estágios iniciais da doença, e por esse motivo, a maioria dos pacientes é diagnosticada somente quando já apresenta várias complicações. O objetivo deste estudo foi avaliar se o rastreio da DRD está sendo realizado de maneira adequada em pacientes com diabetes mellitus tipo 2 (DM2) atendidos na atenção primária à saúde (APS) do Sistema Único de Saúde. Foi realizado um estudo transversal, com duração de cinco meses, na APS dos municípios de Bernardino de Campos e Salto Grande, SP. Os critérios de inclusão foram: diagnóstico de DM2, idade > 18 anos, e ser acompanhado nas unidades participantes do estudo. Um total de 1093 atenderam aos critérios de inclusão e aceitaram participar do estudo. Foi verificado que 398 (36,4%) dos pacientes nunca realizaram os exames de albumina urinária e creatinina, e não tiveram calculados a relação albumina/creatinina em amostra de urina com o cálculo da taxa de filtração glomerular (TFG) estimada pela CKD-EPI a partir da creatinina sérica; 401 (36,7%) dos pacientes realizaram estes exames e tiveram estes índices calculados nos últimos 12 meses. Estes 401 pacientes realizaram estes exames e cálculos de rastreio da DRD uma vez a cada 12 meses nos últimos 5 anos. Os demais pacientes (294; 26,9%) realizaram somente exame de creatinina sérica nos últimos 12 meses. Os resultados demonstraram que o rastreamento da DRD não está sendo realizado de maneira adequada na maioria dos pacientes (AU).
Diabetes Kidney Disease (DRD) is asymptomatic in the early stages of the disease, and for this reason, most patients are diagnosed only when they already have several complications. The aim of this study was to assess whether DRD screening is being carried out properly in patients with type 2 diabetes mellitus (DM2) treated in primary health care (PHC) of the Unified Health System. A cross-sectional study was carried out, lasting five months, in the PHC of the municipalities of Bernardino de Campos and Salto Grande, SP. Inclusion criteria were: diagnosis of DM2, age > 18 years, and being monitored in the units participating in the study. A total of 1093 met the inclusion criteria and agreed to participate in the study. It was found that 398 (36.4%) of the patients had never performed urine albumin and creatinine tests, and they did not calculate the albumin/creatinine ratio in a urine sample, together with the calculation of the glomerular filtration rate (GFR) estimated by CKD-EPI from serum creatinine; in contrast, 401 (36.7%) of the patients underwent these exams and had these indexes calculated in the last 12 months. These 401 patients had these DRD screening tests and calculations performed once every 12 months for the last 5 years. Os demais pacientes (294; 26,9%) realizaram somente exame de creatinina sérica nos últimos 12 meses. Os resultados demonstraram que o rastreamento da DRD não está sendo realizado de maneira adequada na maioria dos pacientes (AU).