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1.
Kidney Blood Press Res ; 46(2): 152-161, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33756482

RESUMO

BACKGROUND: Vitamin D is a hormone regulating not only calcium and phosphate homeostasis but also, at the same time, exerting many other extraskeletal functions via genomic effects (gene transcription) and probably by non-genomic effects as well. Availability is ensured by dietary intake of its precursors and by de novo production via sunlight. Yet, vitamin D deficiency and insufficiency are very common across the globe and are connected to many pathophysiological states, for example, diabetes mellitus, allergies, autoimmune diseases, pregnancy complications, and recently have also been associated with worse COVID-19 clinical outcomes. SUMMARY: In this review, we summarize current knowledge about vitamin D metabolism in general, its role in diabetes mellitus (mainly type 2) and diabetic complications (mainly diabetic kidney disease), and potential therapeutic perspectives including vitamin D signalling as a druggable target. Key Messages: Vitamin D is not only a vitamin but also a hormone involved in many physiological processes. Its insufficiency or deficiency can lead to many pathological states.


Assuntos
Diabetes Mellitus/metabolismo , Nefropatias Diabéticas/metabolismo , Deficiência de Vitamina D/metabolismo , Vitamina D/metabolismo , Animais , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/etiologia , Diabetes Mellitus/fisiopatologia , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/fisiopatologia , Humanos , Transdução de Sinais/efeitos dos fármacos , Vitamina D/uso terapêutico , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/tratamento farmacológico , Deficiência de Vitamina D/fisiopatologia , Vitaminas/metabolismo , Vitaminas/uso terapêutico
2.
Am J Physiol Renal Physiol ; 320(5): F761-F771, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33645318

RESUMO

Inhibitors of the main proximal tubular Na-glucose cotransporter (SGLT2) mitigate diabetic glomerular hyperfiltration and have been approved by the United States Food and Drug Administration for slowing the progression of diabetic kidney disease. It has been proposed that SGLT2 inhibitors improve hard renal outcomes by reducing glomerular capillary pressure (PGC) via a tubuloglomerular feedback (TGF) response to a decrease in proximal reabsorption (Jprox). However, the effect of SGLT2 inhibition on PGC has not been measured. Here, we studied the effects of acute SGLT2 blockade (ertugliflozin) on Jprox and glomerular hemodynamics in two-period micropuncture experiments using streptozotocin-induced diabetic rats fed high- or low-NaCl diets. PGC was measured by direct capillary puncture or computed from tubular stop-flow pressure (PSF). TGF is intact while measuring PGC directly but rendered inoperative when measuring PSF. Acute SGLT2 inhibitor reduced Jprox by ∼30%, reduced PGC by 5-8 mmHg, and reduced glomerular filtration rate (GFR) by ∼25% (all P < 0.0001) but had no effect on PSF. The decrease in PGC was larger with the low-NaCl diet (8 vs. 5 mmHg, P = 0.04) where PGC was higher to begin with (54 vs. 50 mmHg, P = 0.003). Greater decreases in PGC corresponded, unexpectedly, to lesser decreases in GFR (P = 0.04). In conclusion, these results confirm expectations that PGC would decline in response to acute SGLT2 inhibition and that a functioning TGF system is required for this. We infer a contribution of postglomerular vasorelaxation to the TGF responses where decreases in PGC were large and decreases in GFR were small.NEW & NOTEWORTHY It has been theorized that Na-glucose cotransporter (SGLT2) blockade slows progression of diabetic kidney disease by reducing physical strain on the glomerulus. This is the first direct measurement of intraglomerular pressure during SGLT2 blockade. Findings confirmed that SGLT2 blockade does reduce glomerular capillary pressure, that this is mediated through tubuloglomerular feedback, and that the tubuloglomerular feedback response to SGLT2 blockade involves preglomerular vasoconstriction and postglomerular vasorelaxation.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Hemodinâmica/efeitos dos fármacos , Glomérulos Renais/irrigação sanguínea , Circulação Renal/efeitos dos fármacos , Cloreto de Sódio na Dieta/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/fisiopatologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/fisiopatologia , Dieta Hipossódica , Progressão da Doença , Taxa de Filtração Glomerular/efeitos dos fármacos , Masculino , Punções , Ratos Wistar , Reabsorção Renal/efeitos dos fármacos , Cloreto de Sódio na Dieta/metabolismo , Cloreto de Sódio na Dieta/toxicidade , Estreptozocina
3.
Medicine (Baltimore) ; 100(10): e25121, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33725910

RESUMO

BACKGROUND: It is unclear whether there are false positive or negative results in the effects of sodium-glucose transporter 2 (SGLT2) inhibitors on various cardiovascular and renal outcomes in patients with type 2 diabetes. We aimed to explore this issue by a meta-analysis with trial sequential analysis. METHODS: We included randomized trials evaluating the effects of SGLT2 inhibitors on cardiorenal endpoints in type 2 diabetic patients. Eight endpoints evaluated in the study were fatal or nonfatal myocardial infarction (MI), fatal or nonfatal stroke, major adverse cardiovascular events (MACE), cardiovascular death or hospitalization for heart failure (CVD or HHF), all-cause death (ACD), cardiovascular death (CVD), hospitalization for heart failure (HHF), and kidney function progression (KFP). Meta-analysis and trial sequential analysis was conducted for each endpoint. RESULTS: Seven randomized trials of SGLT2 inhibitors were included for pooled analysis. Compared with placebo, SGLT2 inhibitors significantly reduced the risk of MACE (HR 0.89, 95% confidence interval [CI] 0.84-0.94), MI (HR 0.91, 95% CI 0.84-0.99), CVD (HR 0.86, 95% CI 0.79-0.93), CVD or HHF (HR 0.77, 95% CI 0.73-0.82), HHF (HR 0.67, 95% CI 0.62-0.74), KFP (HR 0.63, 95% CI 0.56-0.70), and ACD (HR 0.88, 95% CI 0.83-0.94), whereas SGLT2 inhibitors did not have significant effects on stroke (HR 0.98, 95% CI 0.88-1.09). Trial sequential analyses for MI and stroke showed that cumulative Z curve did not cross trial sequential monitoring boundary and required information size, whereas those for the other 6 endpoints showed that cumulative Z curve crossed trial sequential monitoring boundary and/or required information size. CONCLUSIONS: Compared with placebo, SGLT2 inhibitors conclusively reduce the risk of MACE, CVD or HHF, ACD, CVD, HHF, and KFP in patients with type 2 diabetes, whereas the effects of SGLT2 inhibitors on MI and stroke are not conclusive and need to be further assessed in future studies with the adequate sample size to reject or accept the effect size.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/diagnóstico , Taxa de Filtração Glomerular/efeitos dos fármacos , Insuficiência Cardíaca/epidemiologia , Infarto do Miocárdio/epidemiologia , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Acidente Vascular Cerebral/epidemiologia , Causas de Morte , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/fisiopatologia , Nefropatias Diabéticas/prevenção & controle , Progressão da Doença , Taxa de Filtração Glomerular/fisiologia , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/prevenção & controle , Hospitalização/estatística & dados numéricos , Humanos , Incidência , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Índice de Gravidade de Doença , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Resultado do Tratamento
4.
Int J Mol Sci ; 22(4)2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33546409

RESUMO

Mitochondria are critical organelles that play a key role in cellular metabolism, survival, and homeostasis. Mitochondrial dysfunction has been implicated in the pathogenesis of diabetic kidney disease. The function of mitochondria is critically regulated by several mitochondrial protein kinases, including the phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1). The focus of PINK1 research has been centered on neuronal diseases. Recent studies have revealed a close link between PINK1 and many other diseases including kidney diseases. This review will provide a concise summary of PINK1 and its regulation of mitochondrial function in health and disease. The physiological role of PINK1 in the major cells involved in diabetic kidney disease including proximal tubular cells and podocytes will also be summarized. Collectively, these studies suggested that targeting PINK1 may offer a promising alternative for the treatment of diabetic kidney disease.


Assuntos
Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Suscetibilidade a Doenças , Mitocôndrias/enzimologia , Proteínas Quinases/metabolismo , Animais , Autofagia , Ativação Enzimática , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Humanos , Túbulos Renais/metabolismo , Mitocôndrias/genética , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Podócitos/metabolismo , Proteínas Quinases/genética
5.
Life Sci ; 274: 119226, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33609540

RESUMO

BACKGROUND: O-linked N-acetylglucosaminyltransferase (OGT) is involved in diabetes-related diseases including diabetic nephropathy (DN), and responsible for O-GlcNAcylation. Moreover, O-GlcNAcylation and OGT could be induced by high glucose. Thus, we sought to explore the molecular mechanism of OGT in DN. METHODS: Loss- and gain-functions were conducted to determine the roles of OGT, enhancer of zeste homolog 2 (EZH2), hairy and enhancer of split 1 (HES1) and phosphatase and tensin homolog (PTEN) in the viability, cell cycle and fibrosis of mesangial cells (MCs), followed by the assessment using 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, and Western blot assay (fibrosis-related proteins). The interaction between OGT and EZH2 and the effect on EZH2 glycosylation were verified by chromatin immunoprecipitation (ChIP) and glutathione S-transferase (GST) pull-down assays. EZH2 stability was checked by treatment with cycloheximide. RESULTS: Expression of OGT was repressed in the DN mice and high glucose-treated MCs. Elevated OGT suppressed viability of high glucose-treated MCs, blocked proliferation characterized by repressed cyclin D1, but enhanced p21 levels, and inhibited fibrosis evidenced by reduced levels of fibronectin (FN) and collagen-4 (col-4). OGT interacted with EZH2 and promoted its glycosylation thus stabilizing the EZH2. EZH2 overexpression enhanced the enrichment of EZH2 and histone H3 Lys27 trimethylation (H3K27me3) in the HES1 promoter. HES1 was upregulated and PTEN was downregulated in DN mice. Transduction of lentivirus vector containing overexpression (oe)-OGT alleviated renal injury in DN mice. CONCLUSIONS: Collectively, OGT stabilizes histone methyltransferases EZH2 to regulate HES1/PTEN thus inhibiting DN.


Assuntos
Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/prevenção & controle , Proteína Potenciadora do Homólogo 2 de Zeste/química , N-Acetilglucosaminiltransferases/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Fatores de Transcrição HES-1/metabolismo , Animais , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Regulação para Baixo , Estabilidade Enzimática , Masculino , Camundongos , Camundongos Endogâmicos C57BL , N-Acetilglucosaminiltransferases/genética , PTEN Fosfo-Hidrolase/genética , Fatores de Transcrição HES-1/genética
6.
Toxicol Appl Pharmacol ; 416: 115465, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33631230

RESUMO

Diabetic nephropathy (DN) is a chronic inflammatory renal disease induced by hyperglycemia. Recent studies have implicated cyclin-dependent kinase 9 (CDK9) in inflammatory responses and renal fibrosis. In this study, we explored a potential role of CDK9 in DN by using cultured mouse mesangial cell line SV40 MES-13 and streptozotocin-induced type 1 mouse model of diabetes. We inhibited CDK9 in mice and in cultured cells by a highly selective CDK9 inhibitor, LDC000067 (LDC), and evaluated inflammatory and fibrogenic outcome by mRNA and protein analyses. Our studies show that treatment of diabetic mice with LDC significantly inhibits the levels of inflammatory cytokines and fibrogenic genes in kidney specimens. These reductions were associated with improved renal function. We also found that LDC treatment suppressed MAPK-AP1 activation. We then confirmed the involvement of CDK9 in cultured SV40 MES-13 cells and showed that deficiency in CDK9 prevents glucose-induced inflammatory and fibrogenic proteins. This protection was also afforded by suppression of MAPK-AP1. Taken together, our results how that hyperglycemia activates CDK9-MAPK-AP1 axis in kidneys to induce inflammation and fibrosis, leading to renal dysfunction. Our findings also suggest that CDK9 may serve as a potential therapeutic target for DN.


Assuntos
Anti-Inflamatórios/farmacologia , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Rim/efeitos dos fármacos , Nefrite/prevenção & controle , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Animais , Glicemia/metabolismo , Linhagem Celular , Quinase 9 Dependente de Ciclina/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Nefropatias Diabéticas/enzimologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Fibrose , Mediadores da Inflamação/metabolismo , Rim/enzimologia , Rim/patologia , Masculino , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Nefrite/enzimologia , Nefrite/etiologia , Nefrite/patologia , Fator de Transcrição AP-1/metabolismo
7.
Int J Mol Sci ; 22(4)2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33557007

RESUMO

Diabetic kidney disease (DKD) is a worldwide microvascular complication of type 2 diabetes mellitus (T2DM). From several pathological mechanisms involved in T2DM-DKD, we focused on mitochondria damage induced by hyperglycemia-driven reactive species oxygen (ROS) accumulation and verified whether mesenchymal stem cells (MSCs) anti-oxidative, anti-apoptotic, autophagy modulation, and pro-mitochondria homeostasis therapeutic potential curtailed T2DM-DKD progression. For that purpose, we grew immortalized glomerular mesangial cells (GMCs) in hyper glucose media containing hydrogen peroxide. MSCs prevented these cells from apoptosis-induced cell death, ROS accumulation, and mitochondria membrane potential impairment. Additionally, MSCs recovered GMCs' biogenesis and mitophagy-related gene expression that were downregulated by stress media. In BTBRob/ob mice, a robust model of T2DM-DKD and obesity, MSC therapy (1 × 106 cells, two doses 4-weeks apart, intra-peritoneal route) led to functional and structural kidney improvement in a time-dependent manner. Therefore, MSC-treated animals exhibited lower levels of urinary albumin-to-creatinine ratio, less mesangial expansion, higher number of podocytes, up-regulation of mitochondria-related survival genes, a decrease in autophagy hyper-activation, and a potential decrease in cleaved-caspase 3 expression. Collectively, these novel findings have important implications for the advancement of cell therapy and provide insights into cellular and molecular mechanisms of MSC-based therapy in T2DM-DKD setting.


Assuntos
Nefropatias Diabéticas/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Obesidade/terapia , Animais , Antioxidantes , Caspase 3/metabolismo , Sobrevivência Celular , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Modelos Animais de Doenças , Peróxido de Hidrogênio/metabolismo , Células Mesangiais/metabolismo , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Mitocôndrias/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Estresse Oxidativo , Podócitos/metabolismo , Podócitos/patologia , Espécies Reativas de Oxigênio/metabolismo
8.
Kidney Int ; 99(2): 301-303, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33509348

RESUMO

Risks of kidney failure and heart failure are markedly reduced by inhibition of the sodium glucose cotransporter 2 (SGLT2) in patients with diabetic kidney disease. In a post hoc analysis of the Study of Diabetic Nephropathy with Atrasentan (SONAR) trial, drop-in SGLT2 inhibitor usage during the atrasentan enrichment period led to greater reduction in albuminuria compared with atrasentan alone. These data support the hypothesis of greater longer-term kidney protection by combination SGLT2 inhibition and endothelin A receptor antagonism that could be tested in future clinical trials.


Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Insuficiência Cardíaca , Inibidores do Transportador 2 de Sódio-Glicose , Albuminúria/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/etiologia , Antagonistas dos Receptores de Endotelina , Taxa de Filtração Glomerular , Glucose , Humanos , Sódio , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos
9.
Life Sci ; 269: 119068, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33476631

RESUMO

AIMS: Podocyte apoptosis plays an important role in the pathogenesis of diabetic nephropathy (DN). Astragaloside IV (AS-IV) has been shown to protect against podocyte apoptosis. Here we aim to investigate the mechanism responsible for the protective effects of AS-IV. MAIN METHODS: Diabetic db/db mice and high glucose (HG)-cultured podocytes were treated with AS-IV. Renal function and histopathological changes were measured to evaluate the therapeutic effects of AS-IV against DN. Adenovirus-mediated Klotho overexpression, Klotho siRNA, and PPARγ inhibitor were applied in vitro to investigate the potential mechanism. The expression levels of mRNA and proteins were analyzed by qRT-PCR, western blot or immunofluorescence. Intracellular ROS and mitochondrial superoxide were detected by DHE and MitoSOx Red, respectively. Cell apoptosis was evaluated by TUNEL staining and flow cytometry. KEY FINDINGS: AS-IV improved renal function and ameliorated podocyte injury in db/db mice accompanied with enhanced Klotho expression in glomerular podocytes. In vitro, AS-IV inhibited HG-induced podocyte apoptosis and restored HG-inhibited Klotho expression, whereas Klotho knockdown abrogated the anti-apoptosis action of AS-IV. Further study showed that adenovirus-mediated Klotho overexpression enhanced Forkhead transcription factor O1 (FoxO1)-dependent antioxidant activity and attenuated HG-evoked oxidative stress and apoptosis. AS-IV prevented HG-induced FoxO1 inhibition and oxidative stress, whereas Klotho knockdown reversed these effects. Cotreatment with PPARγ inhibitor T0070907 abolished AS-IV-induced Klotho expression and anti-apoptosis action. SIGNIFICANCE: These data suggested that AS-IV attenuated podocyte apoptosis presumably by inhibiting oxidative stress via activating PPARγ-Klotho-FoxO1 signaling pathway, thereby ameliorating DN. This study provided new insights into the molecular mechanisms of AS-IV against DN.


Assuntos
Apoptose , Nefropatias Diabéticas/prevenção & controle , Proteína Forkhead Box O1/metabolismo , Glucuronidase/metabolismo , PPAR gama/metabolismo , Podócitos/efeitos dos fármacos , Saponinas/farmacologia , Triterpenos/farmacologia , Animais , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Proteína Forkhead Box O1/genética , Regulação da Expressão Gênica , Glucose/metabolismo , Glucuronidase/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , PPAR gama/genética , Podócitos/metabolismo , Podócitos/patologia , Substâncias Protetoras , Transdução de Sinais
10.
Carbohydr Polym ; 251: 117081, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33142624

RESUMO

It seems quite necessary for obtaining effective substances from natural products against the diabetic nephropathic (DN) with the presently clinical problems of accompanying side-effects and lowing life qualities. This work aimed to characterize the primary structure of Coprinus comatus mycelium polysaccharides (CMP) and investigate the abilities against DN in streptozotocin induced mice models. The results indicated that CMP could improve insulin resistance and energy metabolism, and significantly suppress dysfunction on kidney and relieve the renal oxidative stress and inflammation in DN mice. Besides, the western blot results suggested that CMP reversed renal injury by modulating the PTEN/PI3K/Akt and Wnt-1/ß-catenin pathways. The structure analysis indicated the typical characterizations with the major monosaccharide-compositions of galactose, α-pyranose configuration and proper molecular weights of 495.8 kDa possibly contributed to the anti-diabetic nephropathic effects of CMP. The results suggested that polysaccharides form C. comatus could be used as functional foods/drugs on preventing diabetic nephropathy.


Assuntos
Antioxidantes/metabolismo , Coprinus/química , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/tratamento farmacológico , Micélio/química , Polissacarídeos/farmacologia , Animais , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Masculino , Metformina/farmacologia , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Polissacarídeos/química , Via de Sinalização Wnt
11.
Sci Rep ; 10(1): 22206, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33335142

RESUMO

Collagen type VI (COL6) deposition occurs in various glomerular diseases, causing serious pathological damage like nodular lesions. However, the mechanisms underlying the deposition of COL6 remain unclear. In renal biopsy samples, immunohistochemical analyses revealed that COL6 and phosphorylated histone H2AX (γ-H2AX), a DNA damage marker, were detected mainly in diabetic nodular glomerulosclerosis, in which the γ-H2AX-positive area was identified as the independent factor significantly associated with the COL6-positive area (ß: 0.539, t = 2.668). In in vitro studies, COL6 secretion from human renal glomerular endothelial cells (HRGECs) was assessed by measuring the decrease in the cytoplasmic COL6-positive cells and an increase in the amount of COL6 in the culture medium. Mitomycin C (MMc) treatment of HRGECs increased the number of γ-H2AX-positive cells and COL6 secretion, which were suppressed by a specific inhibitor of ataxia telangiectasia and Rad3-related (ATR). MMc-induced COL6 secretion was also suppressed by Annexin A2 (ANXA2) siRNA transfection. Moreover, the inhibition of ATR activity did not induce any extra suppression in the MMc-induced COL6 secretion by ANXA2 siRNA transfected cells. These results confirm that nodular glomerulosclerosis partially results from DNA damage in the glomerulus and that DNA damage-induced COL6 secretion from HRGECs occurs through an ATR and ANXA2-mediated pathway.


Assuntos
Anexina A2/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Dano ao DNA , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Células Endoteliais/metabolismo , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Adulto , Idoso , Biomarcadores , Biópsia , Colágeno Tipo VI/metabolismo , Nefropatias Diabéticas/patologia , Suscetibilidade a Doenças , Feminino , Imunofluorescência , Histonas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Ligação Proteica
12.
Diab Vasc Dis Res ; 17(6): 1479164120971220, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33371732

RESUMO

INTRODUCTION: Diabetes mellitus is a progressive disease with cardiovascular complications. We evaluated the impact of a glucagon like peptide-1 (GLP-1) receptor agonist and sodium glucose cotransporter 2 (SGLT-2) inhibitors dapagliflozin and empagliflozin on renal and cardiac function in type 2 diabetes patients with renal impairment. MATERIALS AND METHODS: A total of 156 patients referred with suboptimal glycemic control were assigned to Group G (GLP-1): n = 72 or Group S (SGLT-2 inhibitor)-dapagliflozin (n = 52) or empagliflozin (n = 32). Renal function was assessed every 3 months for 36 months. Cardiovascular parameters were evaluated every 12 months for 36 months. RESULTS: Compared with baseline, HbA1c and systolic blood pressure significantly decreased in both groups (p < 0.05). The estimated glomerular filtration rate decreased, but without significance. Albuminuria decreased significantly in both groups and then subsequently increased after 30 months in Group S. Diastolic cardiac function, assessed by E/e' or left atrial volume index, decreased only in Group G at 36 months. CONCLUSIONS: The GLP-1 receptor agonist and SGLT-2 inhibitors were effective for glycemic and blood pressure control and for maintaining renal function. The GLP-1 receptor agonist improved diastolic function at 36 months.


Assuntos
Albuminúria/tratamento farmacológico , Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Glucosídeos/uso terapêutico , Incretinas/uso terapêutico , Rim/efeitos dos fármacos , Liraglutida/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Idoso , Albuminúria/diagnóstico , Albuminúria/etiologia , Albuminúria/fisiopatologia , Compostos Benzidrílicos/efeitos adversos , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/fisiopatologia , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/fisiopatologia , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Glucosídeos/efeitos adversos , Humanos , Incretinas/efeitos adversos , Rim/fisiopatologia , Liraglutida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Rigidez Vascular/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos
13.
Medicine (Baltimore) ; 99(50): e23303, 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33327258

RESUMO

Diabetes mellitus (DM) is an independent risk factor for the development of kidney disease. This study assesses the prevalence and determinants of asymptomatic kidney disease in individuals with DM attending health facilities in OR Tambo district, Eastern Cape, South Africa.In this cross-sectional analysis, medical data of 327 individuals receiving care for DM in primary health care centers in OR Tambo district, Eastern Cape between June and November 2013 were reviewed. Significant kidney disease was defined as estimated glomerular filtration rate less than 60 mL/min/1.73 m in accordance with the guidelines of the Society of Endocrinology, Metabolism and Diabetes of South Africa (2017).One-quarter of the 327 participants (n = 80) had significant kidney disease. Female sex [odds ratio (OR) = 5.2; 95% confidence interval (95% CI) 1.2-23.5], never used alcohol (OR = 13.4; 95% CI 2.5-72.1), hypertension (OR = 16.2; 95% CI 2.0-130.0), triglyceride (TG)/high-density lipoprotein (HDL) ratio (OR = 1.2; 95% CI 1.0-1.5), current smoker (OR = 1127.9; 95% CI 162.9-7808.9), former smoker (OR = 13.3; 95% CI 4.1-41.4), and longer duration of diabetes (OR = 4.6; 95% CI 1.6-13.0) were the independent determinants of significant kidney disease among the participants. A significant dose--effect relationship exists between renal disease and smoking status (P < .0001), duration of DM (P < .001), glycemic status (P = .025), and body mass index (P = .003).There is a high rate of undiagnosed kidney disease in this setting, which was independently associated with female sex and presence of other cardiovascular risk factors. Strategic interventions targeting screening and monitoring of renal functions in individuals with DM are urgently needed in this region.


Assuntos
Nefropatias Diabéticas/epidemiologia , Doenças Assintomáticas/epidemiologia , Estudos Transversais , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Feminino , Taxa de Filtração Glomerular , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , África do Sul/epidemiologia
14.
J Postgrad Med ; 66(4): 187-193, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33037171

RESUMO

Background and Aims: Subjects with diabetes are prone to a rapid decline in renal function and major adverse cardiovascular events when they reach chronic kidney disease (CKD) stage 3. This study aimed to identify modifiable risk factors associated with the progression of CKD in this population. Settings and Design: An observational cohort study. Methods and Materials: A total of 320 type 2 diabetic patients with CKD stage 3 registered in the shared-care-system in our hospital in 2010 were regularly followed up for 7 years. Demographic, laboratory, medication, and fundus examination data of these subjects were collected and analyzed. Statistical Analysis Used: Cox regression was used to identify factors associated with changes in CKD stage. Results: During the 7-year follow-up period, 204 cases (63.7%) remained at CKD stage 3 while 79 cases (24.7%) progressed to stage 4 or 5 and 37 cases (11.6%) improved to stage 1 or 2. The change in estimated glomerular filtration rate (eGFR) in the first 2 years and variations in glycated hemoglobin (HbA1c) over 7 years were independent factors of both progression (hazard ratio (HR) 1.098 and 1.710, respectively) and improvement (HR 0.919 and 0.231, respectively) of CKD stage. Variations in systolic blood pressure (SBP) was also found as an independent factor for progression of renal function (HR 1.052). Conclusions: Our results demonstrated that fluctuations in HbA1c and SBP, and changes in eGFR during the first 2 years of treatment were associated with the long-term renal outcomes in type 2 diabetic patients with CKD stage 3.


Assuntos
Pressão Sanguínea/fisiologia , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Hemoglobina A Glicada/metabolismo , Insuficiência Renal Crônica/complicações , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Coortes , Feminino , Taxa de Filtração Glomerular/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Índice de Gravidade de Doença
15.
Medicine (Baltimore) ; 99(35): e21558, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871871

RESUMO

BACKGROUND: As indicated by numerous studies, there exists a relationship between the polymorphism of methylenetetrahydrofolate reductase (MTHFR) and susceptibility to diabetic nephropathy (DN) in various populations; nonetheless, the findings remain inconsistent. Therefore, we carried out a meta-analysis to determine the relationship between the MTHFR gene polymorphism and DN susceptibility. MATERIALS AND METHOD: Related studies were identified from PubMed, Cochrane Library, EMBASE, and the China National Knowledge Infrastructure database (time period: from building the library to October 2019). The strength of the association was examined using odds ratios (ORs) with 95% confidence intervals (95% CIs). RESULTS: The findings illustrated that the C677T gene polymorphism was significantly associated with an enhanced susceptibility to DN compared to that with diabetes mellitus in allelic (OR = 1.64, 95% CI = 1.34-2.00, P < .001), dominant (OR = 1.85, 95% CI = 1.40-2.46, P < .001), codominant (heterozygote: OR = 1.67, 95% CI = 1.27-2.21, P < .001; homozygote: OR = 2.55, 95% CI = 1.82-3.57, P < .001), and recessive (OR = 1.89, 95% CI = 1.50-2.38, P < .001) models of the overall population. Moreover, as compared with the healthy controls, a significantly augmented susceptibility to DN was found in all 5 genetic comparison models (allelic: OR = 2.06, 95% CI = 1.58-2.67, P < .001; dominant: OR = 2.52, 95% CI = 1.73-3.69, P < .001; codominant: OR = 3.78, 95% CI = 2.50-5.70, P < .001; recessive: OR = 2.41, 95% CI = 1.96-2.97, P < .001). Furthermore, stratifying data by ethnicity revealed substantially augmented vulnerability to DN in not only Caucasian but also Asian populations. CONCLUSION: The present study suggests that the C677T polymorphism was associated with an augmented susceptibility to DN.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/epidemiologia , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China/epidemiologia , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Humanos , Fatores de Risco
16.
Life Sci ; 260: 118339, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32841660

RESUMO

AIMS: To design and screen a potent GLP-1/GIP/Gcg receptors triagonist with therapeutic potential in rodent animals with diabetes and obesity. MAIN METHODS: First, we obtained a 12-mer dual GIP/Gcg receptor agonist from a large combinatorial peptide library via high-throughput screening technique and then fused to the Exendin (9-39) to generate a potent GLP-1/GIP/Gcg triagonist. Further site fatty chain modification was performed to improve the druggability via enhancing in vivo stability and cyclic half-life. In vitro signaling and functional assays in cell lines expressing each receptor and in vivo efficacy evaluation in rodent model animals with hyperglycemia and obesity were all carefully performed. KEY FINDINGS: We screened and obtained a potent GLP-1/GIP/Gcg triagonist, termed XFL0, which promotes in vitro GLP-1, GIP, Gcg receptor activation comparable to native GLP-1, GIP and glucagon, respectively. Site-specific fatty acid modification significantly enhanced plasma stability of XFL0 and exhibited no obvious impact on receptor activation. The selected XFL0 conjugates termed XFL6, showed glucose-dependent insulin secretion and improved glucose tolerance by acting on all GLP-1, GIP and Gcg receptors in gene-deficient mice of which the effects were all significantly greater than any single receptor agonist. After chronic treatment in rodent animals with diabetes and obesity, XFL6 potently decreased body weight and food intake, ameliorated the hyperglycemia and hemoglobin A1c levels as well as the lipid metabolism and diabetic nephropathy related disorders. SIGNIFICANCE: XFL6, as a novel GLP-1/GIP/Gcg receptor triagonist, held potential to deliver outstanding improvement in correcting hyperglycemia, obesity and diabetic nephropathy.


Assuntos
Nefropatias Diabéticas/prevenção & controle , Desenho de Fármacos , Polipeptídeo Inibidor Gástrico/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Glucagon/agonistas , Hiperglicemia/prevenção & controle , Obesidade/prevenção & controle , Animais , Diabetes Mellitus Experimental/fisiopatologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Polipeptídeo Inibidor Gástrico/fisiologia , Glucagon/fisiologia , Receptor do Peptídeo Semelhante ao Glucagon 1/fisiologia , Hiperglicemia/etiologia , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia
17.
Life Sci ; 258: 118160, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32730837

RESUMO

AIMS: Diabetic kidney disease (DKD) is a major prevalent chronic microvascular complication of type 2 diabetes (T2D). However, the present diagnostic indicators have limitations in the early diagnosis of DKD. This study concentrated on the sensitive and specific biomarkers in early diagnosis of DKD by metabolomics. MATERIALS AND METHODS: In this cross-sectional study, we performed a UPLC-MS based nontargeted metabolomics assay to profile the urinary metabolites in patients with DKD. Principal Component Analysis (PCA) and orthogonal partial least square discriminant analysis (OPLS-DA) were used for screening out the metabolomic variables. KEY FINDINGS: A total of 147 urinary metabolites were identified and 5 metabolic pathways were correlated with DKD pathophysiology. Pantothenate and coenzyme A biosynthesis pathway alteration was found the most prominent in DKD subjects. 4 metabolites, including dihydrouracil, ureidopropionic acid, pantothenic acid (PA), and adenosine 3',5'-diphosphate involved in pantothenate and CoA biosynthesis were significantly down-regulated. SIGNIFICANCE: Our finding indicates that PA would be served as a novel predictive biomarker associated with DKD development and progression. Furthermore, our results provide a promising prospect that PA and CoA biosynthesis pathway can be potential therapeutic targets for DKD treatment.


Assuntos
Vias Biossintéticas , Coenzima A/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/metabolismo , Ácido Pantotênico/metabolismo , Cromatografia Líquida de Alta Pressão , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/urina , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/urina , Feminino , Humanos , Masculino , Espectrometria de Massas , Metaboloma , Pessoa de Meia-Idade
18.
Life Sci ; 258: 118146, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32721462

RESUMO

OBJECTIVE: To investigate protective efficacies and mechanisms of dencichine on diabetic kidney injury via in vitro and in vivo assays. METHODS: Effects of dencichine on hydrogen peroxide (H2O2) induced oxidative damage in HK-2 renal cells were assessed by CCK-8 method. Forty streptozotocin (STZ)-induced diabetic rats with kidney injury were randomly divided into negative control group, three doses of dencichine (40, 80 and 160 mg/kg) groups. Blood biochemical and kidney related indexes as well adrenal morphological changes, apoptosis and autophagy related markers of diabetic rats were measured. RESULTS: Cell viability of HK-2 cells with oxidative damage induced by H2O2 was significantly improved by dencichine with 160 µg/mL for 43.7% and 320 µg/mL for 52.9% compared with control. Moreover, the decreased reactive oxygen species (ROS), and increased intracellular antioxidant enzymes including GPX1, SOD2 and GSH were showed in dencichine groups. In addition, incubation of dencichine in HK-2 cells promoted the increase of p-AMPK, BCL2, LC3, decreased activation of p-mTOR, BAX and Caspase 3. Chronic treatment of dencichine improved the STZ-induced diabetic characteristics of model rats. Further histopathological examination of renal tissues revealed 12-week treatment of dencichine effectively improved the morphology of nephropathy in diabetic rats. Moreover, dencichine also ameliorated excessive oxidation stress, down-regulated renal cell apoptosis and fibrosis related proteins, thereby protected renal tissues in diabetic rats. CONCLUSION: Dencichine ameliorated STZ-induced kidney injury mainly through inhibiting oxidative stress, reducing renal fibrosis, increasing autophagy, and reducing the renal cell apoptosis related proteins to protect nephrocytes and decrease renal tissue damage.


Assuntos
Diamino Aminoácidos/uso terapêutico , Antioxidantes/uso terapêutico , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/tratamento farmacológico , Rim/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Fibrose , Humanos , Rim/metabolismo , Rim/patologia , Masculino , Ratos , Ratos Sprague-Dawley
20.
Nat Rev Nephrol ; 16(7): 377-390, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32398868

RESUMO

Diabetes is one of the fastest growing diseases worldwide, projected to affect 693 million adults by 2045. Devastating macrovascular complications (cardiovascular disease) and microvascular complications (such as diabetic kidney disease, diabetic retinopathy and neuropathy) lead to increased mortality, blindness, kidney failure and an overall decreased quality of life in individuals with diabetes. Clinical risk factors and glycaemic control alone cannot predict the development of vascular complications; numerous genetic studies have demonstrated a clear genetic component to both diabetes and its complications. Early research aimed at identifying genetic determinants of diabetes complications relied on familial linkage analysis suited to strong-effect loci, candidate gene studies prone to false positives, and underpowered genome-wide association studies limited by sample size. The explosion of new genomic datasets, both in terms of biobanks and aggregation of worldwide cohorts, has more than doubled the number of genetic discoveries for both diabetes and diabetes complications. We focus herein on genetic discoveries for diabetes and diabetes complications, empowered primarily through genome-wide association studies, and emphasize the gaps in research for taking genomic discovery to the next level.


Assuntos
Complicações do Diabetes/genética , Diabetes Mellitus Tipo 2/genética , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/genética , Complicações do Diabetes/etiologia , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/genética , Neuropatias Diabéticas/etiologia , Neuropatias Diabéticas/genética , Retinopatia Diabética/etiologia , Retinopatia Diabética/genética , Humanos
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