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2.
Carbohydr Polym ; 339: 122275, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-38823933

RESUMO

Diabetic kidney disease (DKD) is the main cause of end-stage renal disease, and few therapeutic options are available. The root of Achyranthis bidentatae (AB) is commonly used for DKD treatment in Traditional Chinese medicine. However, its mechanisms are still unclear. Here, a graminan type fructan ABPW1 with molecular weight of 3998 Da was purified from AB. It was composed of ß-1,2-linked Fruf, ß-2,6-linked-Fruf and ß-1,2,6-linked-Fruf backbone, and terminated with T-Glcp and 2-Fruf residues. ABPW1 protected against kidney injuries and intestinal barrier disruption in Streptozotocin (STZ)/High fat diet (HFD) mice. It could modulate gut microbiota composition, evidenced by a rise in the abundance of Bacteroide and decreases of Rikenella, Alistipes, Laedolimicola and Faecalibaculum. ABPW1 intervention promoted short chain fatty acids (SCFAs) production in STZ/HFD mice, especially propionate and isobutyric acid. Antibiotic treatment further demonstrated the key role of gut microbiota in the renal protective action of ABPW1. In addition, in vitro simulated digestion and fermentation together with in vivo fluorescent labeling studies demonstrated ABPW1 was indigestible in upper digestive tract but could reach the colon and be degraded into SCFAs by gut microbiota there. Overall, these data suggested ABPW1 has the potential application on DKD prevention.


Assuntos
Achyranthes , Diabetes Mellitus Experimental , Nefropatias Diabéticas , Frutanos , Microbioma Gastrointestinal , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Achyranthes/química , Camundongos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Masculino , Frutanos/farmacologia , Frutanos/química , Camundongos Endogâmicos C57BL , Dieta Hiperlipídica/efeitos adversos , Estreptozocina , Rim/efeitos dos fármacos , Rim/patologia , Ácidos Graxos Voláteis/metabolismo
3.
Eur J Pharmacol ; 976: 176699, 2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-38825302

RESUMO

Clinically, statins have long been used for the prevention and treatment of chronic renal diseases, however, the underlying mechanisms are not fully elucidated. The present study investigated the effects of atorvastatin on diabetes renal injury and ferroptosis signaling. A mouse model of diabetes was established by the intraperitoneal injection of streptozotocin (50 mg/kg/day) plus a high fat diet with or without atorvastatin treatment. Diabetes mice manifested increased plasma glucose and lipid profile, proteinuria, renal injury and fibrosis, atorvastatin significantly lowered plasma lipid profile, proteinuria, renal injury in diabetes mice. Atorvastatin reduced renal reactive oxygen species (ROS), iron accumulation and renal expression of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), transferrin receptor 1 (TFR1), and increased renal expression of glutathione peroxidase 4 (GPX4), nuclear factor erythroid 2-related factor (NRF2) and ferritin heavy chain (FTH) in diabetes mice. Consistent with the findings in vivo, atorvastatin prevented high glucose-induced ROS formation and Fe2+ accumulation, an increase in the expression of 4-HNE, MDA and TFR1, and a decrease in cell viability and the expression of NRF2, GPX4 and FTH in HK2 cells. Atorvastatin also reversed ferroptosis inducer erastin-induced ROS production, intracellular Fe2+ accumulation and the changes in the expression of above-mentioned ferroptosis signaling molecules in HK2 cells. In addition, atorvastatin alleviated high glucose- or erastin-induced mitochondria injury. Ferroptosis inhibitor ferrostatin-1 and antioxidant N-acetylcysteine (NAC) equally reversed the expression of high glucose-induced ferroptosis signaling molecules. Our data support the notion that statins can inhibit diabetes-induced renal oxidative stress and ferroptosis, which may contribute to statins protection of diabetic nephropathy.


Assuntos
Atorvastatina , Nefropatias Diabéticas , Ferroptose , Estresse Oxidativo , Espécies Reativas de Oxigênio , Transdução de Sinais , Ferroptose/efeitos dos fármacos , Animais , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Atorvastatina/farmacologia , Atorvastatina/uso terapêutico , Masculino , Transdução de Sinais/efeitos dos fármacos , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/complicações , Camundongos Endogâmicos C57BL , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Linhagem Celular , Fenilenodiaminas/farmacologia , Fenilenodiaminas/uso terapêutico
5.
Am J Physiol Renal Physiol ; 326(6): F1054-F1065, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38695075

RESUMO

Diabetic nephropathy remains the leading cause of end-stage kidney disease in many countries, and additional therapeutic targets are needed to prevent its development and progression. Some angiogenic factors are involved in the pathogenesis of diabetic nephropathy. Vasohibin-2 (VASH2) is a novel proangiogenic factor, and our previous study showed that glomerular damage is inhibited in diabetic Vash2 homozygous knockout mice. Therefore, we established a VASH2-targeting peptide vaccine as a tool for anti-VASH2 therapy in diabetic nephropathy. In this study, the preventive effects of the VASH2-targeting peptide vaccine against glomerular injury were examined in a streptozotocin (STZ)-induced diabetic mouse model. The mice were subcutaneously injected with the vaccine at two doses 2 wk apart and then intraperitoneally injected with 50 mg/kg STZ for 5 consecutive days. Glomerular injury was evaluated 20 wk after the first vaccination. Treatment with the VASH2-targeting peptide vaccine successfully induced circulating anti-VASH2 antibody without inflammation in major organs. Although the vaccination did not affect blood glucose levels, it significantly prevented hyperglycemia-induced increases in urinary albumin excretion and glomerular volume. The vaccination did not affect increased VASH2 expression but significantly inhibited renal angiopoietin-2 (Angpt2) expression in the diabetic mice. Furthermore, it significantly prevented glomerular macrophage infiltration. The preventive effects of vaccination on glomerular injury were also confirmed in db/db mice. Taken together, the results of this study suggest that the VASH2-targeting peptide vaccine may prevent diabetic glomerular injury in mice by inhibiting Angpt2-mediated microinflammation.NEW & NOTEWORTHY This study demonstrated preventive effects of VASH2-targeting peptide vaccine therapy on albuminuria and glomerular microinflammation in STZ-induced diabetic mouse model by inhibiting renal Angpt2 expression. The vaccination was also effective in db/db mice. The results highlight the importance of VASH2 in the pathogenesis of early-stage diabetic nephropathy and the practicability of anti-VASH2 strategy as a vaccine therapy.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Vacinas de Subunidades Antigênicas , Animais , Nefropatias Diabéticas/prevenção & controle , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/imunologia , Masculino , Vacinas de Subunidades Antigênicas/farmacologia , Vacinas de Subunidades Antigênicas/imunologia , Albuminúria/prevenção & controle , Camundongos Endogâmicos C57BL , Angiopoietina-2/metabolismo , Camundongos , Glomérulos Renais/patologia , Glomérulos Renais/metabolismo , Glomérulos Renais/imunologia , Proteínas Angiogênicas/metabolismo , Vacinas de Subunidades Proteicas
6.
Pak J Pharm Sci ; 37(1): 65-70, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38741401

RESUMO

Diabetic nephropathy (DN), a micro vascular complication of diabetes, is the main cause of end-stage renal disease, with a morbidity over 40% of diabetes. High glucose and lipid metabolism dysfunction are the leading cause of the development of DN. Previous study demonstrated that increased expression or activation of SREBPs in models of DN. Leonuride (LE), as an active constituent of Leonurus japonicus Houttuyn, has multiple biological activities, including antioxidant and anti-inflammatory effects. Previous studies showed that increasing the degradation of mature SREBPs is a robust way of lowering lipids and improve lipid metabolism dysfunction. However, effective regulation method of SREBPs degradation are still lacking. Herein, this study indicated that LE can effectively improve glucose and lipid metabolism disorders. In addition, the kidney function was also improved by inhibition of SREBPs activities in streptozocin (STZ)-induced type II diabetic mice. To our knowledge, this is the first time to describe the detailed mechanism of LE on the inhibition of precursor SREBPs, which would present a new direction for diabetic nephropathy treatment.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/prevenção & controle , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Masculino , Camundongos , Metabolismo dos Lipídeos/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Transdução de Sinais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações
7.
Carbohydr Res ; 540: 109125, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38703663

RESUMO

Di-d-psicose anhydride (DPA), derived from functional rare saccharide as d-psicose, is investigated for its strong chelating ability. Methylglyoxal (MGO), an important precursor of advanced glycation end-products (AGEs), promotes obesity, and causes complications such as diabetic nephropathy. On mesangial cells, DPA can substantially reduce the negative effects of MGO. DPA effectively trapping MGO in mesangial cells. The bonding properties of the DPA-MGO adduct were discussed by mass spectrometry and nuclear magnetic resonance (NMR). The NMR spectra of the DPA-MGO adduct provide evidence for chelation bonding. The inhibition of AGE formation and the mass spectrometry results of the DPA-MGO adduct indicate that DPA can scavenge MGO at a molar ratio of 1:1. DPA suppressed 330 % of the up-regulated receptor for an AGEs protein expression to a normal level and restored the suppressed glyoxalase 1 level to 86 % of the normal group. This research provides important evidence and theoretical basis for the development of AGE inhibitors derived from rare saccharide.


Assuntos
Nefropatias Diabéticas , Produtos Finais de Glicação Avançada , Aldeído Pirúvico , Aldeído Pirúvico/química , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/prevenção & controle , Produtos Finais de Glicação Avançada/metabolismo , Produtos Finais de Glicação Avançada/antagonistas & inibidores , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/metabolismo , Lactoilglutationa Liase/antagonistas & inibidores , Lactoilglutationa Liase/metabolismo , Humanos , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Receptor para Produtos Finais de Glicação Avançada/antagonistas & inibidores , Anidridos/química , Quelantes/química , Quelantes/farmacologia
8.
Mol Biol Rep ; 51(1): 677, 2024 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-38796641

RESUMO

BACKGROUND: One of the main causes of diabetic nephropathy is oxidative stress induced by hyperglycemia. Apelin inhibits insulin secretion. Besides, renal expression of TGF-ß is increased in diabetes mellitus (DM). The preventive effect of quercetin (Q) against renal functional disorders and tissue damage developed by DM in rats was assessed. METHODS: Forty male Wistar rats were grouped into normal control (NC), normal + quercetin (NQ: quercetin, 50 mg/kg/day by gavage), diabetic control (DC: streptozotocin, 65 mg/kg, i.p.), diabetic + quercetin pretreatment (D + Qpre), and diabetic + quercetin post-treatment (D + Qpost). All samples (24-hour urine, plasma, pancreatic, and renal tissues) were obtained at the terminal of the experiment. RESULTS: Compared to NC and NQ groups, DM ended in elevated plasma and glucose levels, decreased plasma insulin level, kidney dysfunction, augmented levels of malondialdehyde, decreased level of reduced glutathione, reduced enzymatic activities of superoxide dismutase and catalase, elevated gene expression levels of apelin and TGF-ß, also renal and pancreatic histological damages. Quercetin administration diminished entire the changes. However, the measure of improvement in the D + Qpre group was higher than that of the D + Qpost group. CONCLUSION: Quercetin prevents renal dysfunction induced by DM, which might be related to the diminution of lipid peroxidation, strengthening of antioxidant systems, and prevention of the apelin/ TGF-ß signaling pathway.


Assuntos
Apelina , Diabetes Mellitus Experimental , Nefropatias Diabéticas , Rim , Estresse Oxidativo , Quercetina , Ratos Wistar , Fator de Crescimento Transformador beta , Animais , Quercetina/farmacologia , Ratos , Masculino , Fator de Crescimento Transformador beta/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/prevenção & controle , Nefropatias Diabéticas/tratamento farmacológico , Apelina/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Insulina/metabolismo , Insulina/sangue , Diabetes Mellitus Tipo 1/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos
9.
BMJ Open Diabetes Res Care ; 12(3)2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38816203

RESUMO

INTRODUCTION: The Look AHEAD randomized clinical trial reported that an 8-year intensive lifestyle intervention (ILI) compared with diabetes support and education (DSE) in adults aged 45-76 years with type 2 diabetes and overweight/obesity delayed kidney disease progression. Here, we report long-term post-intervention follow-up for the trial's secondary outcome of kidney disease. RESEARCH DESIGN AND METHODS: We examined effects of ILI (n=2570) versus DSE (n=2575) on decline in estimated glomerular filtration rate (eGFR) to <45 mL/min/1.73 m2 or need for kidney replacement therapy (KRT: dialysis or kidney transplant) during intervention and post-intervention follow-up (median 15.6 years overall). RESULTS: Incidence of eGFR <45 mL/min/1.73 m2 was lower in ILI during the intervention (HR=0.80, 95% CI=0.66 to 0.98) but not post-intervention (HR=1.03, 0.86 to 1.23) or overall (HR=0.92, 0.80 to 1.04). There were no significant treatment group differences in KRT. In prespecified subgroup analyses, age×treatment interactions were significant over total follow-up: p=0.001 for eGFR <45 mL/min/1.73 m2 and p=0.01 for KRT. The 2205 participants aged >60 years at baseline had benefit in both kidney outcomes during intervention and overall (HR=0.75, 0.62 to 0.90 for eGFR <45 mL/min/1.73 m2; HR=0.62, 0.43 to 0.91 for KRT). The absolute treatment effects were greater post-intervention: ILI reduced the rate of eGFR <45 mL/min/1.73 m2 by 0.46 and 0.76 cases/100 person-years during and post-intervention, respectively; and reduced KRT by 0.15 and 0.21 cases/100 person-years. The younger participants experienced no such post-intervention benefits. CONCLUSIONS: ILI reduced kidney disease progression during and following the active intervention in persons aged ≥60 years. ILI should be considered for reducing kidney disease incidence in older persons with type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Taxa de Filtração Glomerular , Estilo de Vida , Obesidade , Sobrepeso , Humanos , Diabetes Mellitus Tipo 2/terapia , Diabetes Mellitus Tipo 2/complicações , Pessoa de Meia-Idade , Masculino , Feminino , Idoso , Obesidade/terapia , Sobrepeso/terapia , Sobrepeso/complicações , Seguimentos , Progressão da Doença , Nefropatias Diabéticas/terapia , Nefropatias Diabéticas/prevenção & controle , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/epidemiologia , Comportamento de Redução do Risco , Prognóstico
10.
Zhongguo Zhong Yao Za Zhi ; 49(5): 1249-1254, 2024 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-38621971

RESUMO

The chemical constituents of Draconis Sanguis were preliminarily studied by macroporous resin, silica gel, dextran gel, and high-performance liquid chromatography. One retro-dihydrochalcone, four flavonoids, and one stilbene were isolated. Their chemical structures were identified as 4-hydroxy-2,6-dimethoxy-3-methyldihydrochalcone(1), 4'-hydroxy-5,7-dimethoxy-8-methylflavan(2), 7-hydroxy-4',5-dimethoxyflavan(3),(2S)-7-hydroxy-5-methoxy-6-methylflavan(4),(2S)-7-hydroxy-5-methoxyflavan(5), and pterostilbene(6) by modern spectroscopy, physicochemical properties, and literature comparison. Compound 1 was a new compound. Compounds 2 and 6 were first found in the Arecaceae family. Compound 5 had the potential to prevent and treat diabetic kidney disease.


Assuntos
Arecaceae , Diabetes Mellitus , Nefropatias Diabéticas , Medicamentos de Ervas Chinesas , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Flavonoides/análise , Medicamentos de Ervas Chinesas/química , Cromatografia Líquida de Alta Pressão/métodos
11.
PLoS One ; 19(4): e0301992, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38640098

RESUMO

BACKGROUND AND OBJECTIVE: Diabetic neuropathy (DN) is a complex type of diabetes. The underlying cause of diabetic nephropathy remains unclear and may be due to a variety of pathological conditions resulting in kidney failure. This study examines the protective effect of the methanolic extract of Spilanthes filicaulis leaves (MESFL) in fructose-fed streptozotocin (STZ)-induced diabetic nephropathy and the associated pathway. METHODS: Twenty-five rats were equally divided randomly into five categories: Control (C), diabetic control, diabetic + metformin (100 mg/kg), diabetic + MESFL 150 mg/kg bw, and diabetic + MESFL 300 mg/kg bw. After 15 days, the rats were evaluated for fasting blood glucose (FBG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), urea, uric acid, serum creatinine, reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and lipid peroxidation (MDA). Gene expression levels of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), cAMP response element-binding (CREB), cFOS and the antiapoptotic protein Bcl-2 were examined. RESULTS: We observed that MESFL at 150 and 300 mg/kg bw significantly downregulated the protein expression of cAMP, PKA, CREB, and cFOS and upregulated the Bcl-2 gene, suggesting that the nephroprotective action of MESFL is due to the suppression of the cAMP/PKA/CREB/cFOS signaling pathway. In addition, MESFL increases SOD and CAT activities and GSH levels, reduces MDA levels, and reduces renal functional indices (ALP, urea, uric acid, and creatinine). CONCLUSION: Therefore, our results indicate that MESFL alleviates the development of diabetic nephropathy via suppression of the cAMP/PKA/CREB/cFOS pathways.


Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Ratos , Animais , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Nefropatias Diabéticas/metabolismo , Estreptozocina/farmacologia , Rim/patologia , Ácido Úrico/metabolismo , Superóxido Dismutase/metabolismo , Estresse Oxidativo , Diabetes Mellitus/patologia
12.
Int J Mol Sci ; 25(7)2024 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-38612417

RESUMO

Diabetic nephropathy (DN) is a serious complication of diabetes, and its progression is influenced by factors like oxidative stress, inflammation, cell death, and fibrosis. Compared to drug treatment, exercise offers a cost-effective and low-risk approach to slowing down DN progression. Through multiple ways and mechanisms, exercise helps to control blood sugar and blood pressure and reduce serum creatinine and albuminuria, thereby alleviating kidney damage. This review explores the beneficial effects of exercise on DN improvement and highlights its potential mechanisms for ameliorating DN. In-depth understanding of the role and mechanism of exercise in improving DN would pave the way for formulating safe and effective exercise programs for the treatment and prevention of DN.


Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Humanos , Nefropatias Diabéticas/prevenção & controle , Albuminúria , Glicemia , Pressão Sanguínea , Morte Celular
13.
Cochrane Database Syst Rev ; 4: CD006257, 2024 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-38682786

RESUMO

BACKGROUND: Guidelines suggest that adults with diabetes and kidney disease receive treatment with angiotensin-converting-enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB). This is an update of a Cochrane review published in 2006. OBJECTIVES: We compared the efficacy and safety of ACEi and ARB therapy (either as monotherapy or in combination) on cardiovascular and kidney outcomes in adults with diabetes and kidney disease. SEARCH METHODS: We searched the Cochrane Kidney and Transplants Register of Studies to 17 March 2024 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: We included studies evaluating ACEi or ARB alone or in combination, compared to each other, placebo or no treatment in people with diabetes and kidney disease. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the risk of bias and extracted data. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) or standardised mean difference (SMD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: One hundred and nine studies (28,341 randomised participants) were eligible for inclusion. Overall, the risk of bias was high. Compared to placebo or no treatment, ACEi may make little or no difference to all-cause death (24 studies, 7413 participants: RR 0.91, 95% CI 0.73 to 1.15; I2 = 23%; low certainty) and with similar withdrawals from treatment (7 studies, 5306 participants: RR 1.03, 95% CI 0.90 to 1.19; I2 = 0%; low certainty). ACEi may prevent kidney failure (8 studies, 6643 participants: RR 0.61, 95% CI 0.39 to 0.94; I2 = 0%; low certainty). Compared to placebo or no treatment, ARB may make little or no difference to all-cause death (11 studies, 4260 participants: RR 0.99, 95% CI 0.85 to 1.16; I2 = 0%; low certainty). ARB have uncertain effects on withdrawal from treatment (3 studies, 721 participants: RR 0.85, 95% CI 0.58 to 1.26; I2 = 2%; low certainty) and cardiovascular death (6 studies, 878 participants: RR 3.36, 95% CI 0.93 to 12.07; low certainty). ARB may prevent kidney failure (3 studies, 3227 participants: RR 0.82, 95% CI 0.72 to 0.94; I2 = 0%; low certainty), doubling of serum creatinine (SCr) (4 studies, 3280 participants: RR 0.84, 95% CI 0.72 to 0.97; I2 = 32%; low certainty), and the progression from microalbuminuria to macroalbuminuria (5 studies, 815 participants: RR 0.44, 95% CI 0.23 to 0.85; I2 = 74%; low certainty). Compared to ACEi, ARB had uncertain effects on all-cause death (15 studies, 1739 participants: RR 1.13, 95% CI 0.68 to 1.88; I2 = 0%; low certainty), withdrawal from treatment (6 studies, 612 participants: RR 0.91, 95% CI 0.65 to 1.28; I2 = 0%; low certainty), cardiovascular death (13 studies, 1606 participants: RR 1.15, 95% CI 0.45 to 2.98; I2 = 0%; low certainty), kidney failure (3 studies, 837 participants: RR 0.56, 95% CI 0.29 to 1.07; I2 = 0%; low certainty), and doubling of SCr (2 studies, 767 participants: RR 0.88, 95% CI 0.52 to 1.48; I2 = 0%; low certainty). Compared to ACEi plus ARB, ACEi alone has uncertain effects on all-cause death (6 studies, 1166 participants: RR 1.08, 95% CI 0.49 to 2.40; I2 = 20%; low certainty), withdrawal from treatment (2 studies, 172 participants: RR 0.78, 95% CI 0.33 to 1.86; I2 = 0%; low certainty), cardiovascular death (4 studies, 994 participants: RR 3.02, 95% CI 0.61 to 14.85; low certainty), kidney failure (3 studies, 880 participants: RR 1.36, 95% CI 0.79 to 2.32; I2 = 0%; low certainty), and doubling of SCr (2 studies, 813 participants: RR 1.14, 95% CI 0.70 to 1.85; I2 = 0%; low certainty). Compared to ACEi plus ARB, ARB alone has uncertain effects on all-cause death (7 studies, 2607 participants: RR 1.02, 95% CI 0.76 to 1.37; I2 = 0%; low certainty), withdrawn from treatment (3 studies, 1615 participants: RR 0.81, 95% CI 0.53 to 1.24; I2 = 0%; low certainty), cardiovascular death (4 studies, 992 participants: RR 3.03, 95% CI 0.62 to 14.93; low certainty), kidney failure (4 studies, 2321 participants: RR 1.15, 95% CI 0.67 to 1.95; I2 = 29%; low certainty), and doubling of SCr (3 studies, 2252 participants: RR 1.18, 95% CI 0.85 to 1.64; I2 = 0%; low certainty). Comparative effects of different ACEi or ARB and low-dose versus high-dose ARB were rarely evaluated. No study compared different doses of ACEi. Adverse events of ACEi and ARB were rarely reported. AUTHORS' CONCLUSIONS: ACEi or ARB may make little or no difference to all-cause and cardiovascular death compared to placebo or no treatment in people with diabetes and kidney disease but may prevent kidney failure. ARB may prevent the doubling of SCr and the progression from microalbuminuria to macroalbuminuria compared with a placebo or no treatment. Despite the international guidelines suggesting not combining ACEi and ARB treatment, the effects of ACEi or ARB monotherapy compared to dual therapy have not been adequately assessed. The limited data availability and the low quality of the included studies prevented the assessment of the benefits and harms of ACEi or ARB in people with diabetes and kidney disease. Low and very low certainty evidence indicates that it is possible that further studies might provide different results.


Assuntos
Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina , Nefropatias Diabéticas , Progressão da Doença , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Viés , Causas de Morte , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/prevenção & controle , Quimioterapia Combinada
14.
Life Sci ; 347: 122667, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38670449

RESUMO

BACKGROUND: Zinc deficiency is strongly correlated with prolonged diabetes mellitus and diabetic nephropathy (DN). Previously, glucose-lowering, insulinomimetic, and ß-cell proliferative activities of zinc oxide nanoparticles (ZON) have been reported. Considering these pleiotropic effects, we hypothesized that ZON modulates multiple cellular pathways associated with necroptosis, inflammation, and renal fibrosis, which are involved in progressive loss of renal function. AIM: This study evaluated the effect of ZON on renal function, leading to the alleviation of DN in streptozotocin (STZ)-induced type 1 diabetic Wistar rats and proposed a probable mechanism for its activity. METHODS: Wistar rats (n = 6/group) were used as healthy controls, diabetic controls, diabetic rats treated with ZON (1, 3, and 10 mg/kg), and insulin controls. Urine and serum biochemical parameters, glomerular filtration rate (GFR), and renal histology were also evaluated. Cultured E11 podocytes were evaluated in vitro for markers of oxidative stress, proteins associated with the loss of renal function, and genes associated with renal damage. KEY FINDINGS: STZ-treated rats receiving oral doses of ZON showed enhanced renal function, with no histological alterations in the kidney tissue. ZON inhibited the TGF-ß/Samd3 pathway in renal fibrosis; blocked Ripk1/Ripk3/Mlkl mediated necroptosis and protected against hyperglycemia-induced pyroptosis. In E11 podocytes, ZON reduced oxidative stress under high glucose conditions and retained podocyte-specific proteins. SIGNIFICANCE: A probable mechanism by which ZON prevents DN has been proposed, suggesting its use as a complementary therapeutic agent for the treatment of diabetic complications. To the best of our knowledge, this is the first study to demonstrate the in vitro effects of ZON in cultured podocytes.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Estresse Oxidativo , Ratos Wistar , Óxido de Zinco , Animais , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Nefropatias Diabéticas/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Masculino , Óxido de Zinco/farmacologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Nanopartículas , Podócitos/efeitos dos fármacos , Podócitos/metabolismo , Podócitos/patologia , Fibrose , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo , Estreptozocina , Transdução de Sinais/efeitos dos fármacos
15.
Diabetes Obes Metab ; 26(6): 2046-2053, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38516874

RESUMO

Aggressive therapy of diabetic kidney disease (DKD) can not only slow the progression of DKD to renal failure but, if utilized at an early enough stage of DKD, can also stabilize and/or reverse the decline in renal function. The currently recognized standard of therapy for DKD is blockade of the renin-angiotensin system with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). However, unless utilized at a very early stage, monotherapy with these drugs in DKD will only prevent or slow the progression of DKD and will neither stabilize nor reverse the progression of DKD to renal decompensation. Recently, the addition of a sodium-glucose cotransporter-2 inhibitor and/or a mineralocorticoid receptor blocker to ACE inhibitors or ARBs has been clearly shown to further decelerate the decline in renal function. The use of glucagon-like peptide-1 (GLP-1) agonists shown promise in decelerating the progression of DKD. Other drugs that may aid in the deceleration the progression of DKD are dipeptidyl peptidase-4 inhibitors, pentoxifylline, statins, and vasodilating beta blockers. Therefore, aggressive therapy with combinations of these drugs (stacking) should improve the preservation of renal function in DKD.


Assuntos
Inibidores da Enzima Conversora de Angiotensina , Nefropatias Diabéticas , Quimioterapia Combinada , Antagonistas de Receptores de Mineralocorticoides , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Progressão da Doença , Sistema Renina-Angiotensina/efeitos dos fármacos , Resultado do Tratamento , Antagonistas de Receptores de Angiotensina/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/agonistas , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Hipoglicemiantes/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Inibidores da Dipeptidil Peptidase IV/uso terapêutico
16.
Cardiovasc Diabetol ; 23(1): 50, 2024 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-38302978

RESUMO

BACKGROUND: Diabetes mellitus is a chronic disease which is detrimental to cardiovascular health, often leading to secondary microvascular complications, with huge global health implications. Therapeutic interventions that can be applied to multiple vascular beds are urgently needed. Diabetic retinopathy (DR) and diabetic kidney disease (DKD) are characterised by early microvascular permeability changes which, if left untreated, lead to visual impairment and renal failure, respectively. The heparan sulphate cleaving enzyme, heparanase, has previously been shown to contribute to diabetic microvascular complications, but the common underlying mechanism which results in microvascular dysfunction in conditions such as DR and DKD has not been determined. METHODS: In this study, two mouse models of heparan sulphate depletion (enzymatic removal and genetic ablation by endothelial specific Exotosin-1 knock down) were utilized to investigate the impact of endothelial cell surface (i.e., endothelial glycocalyx) heparan sulphate loss on microvascular barrier function. Endothelial glycocalyx changes were measured using fluorescence microscopy or transmission electron microscopy. To measure the impact on barrier function, we used sodium fluorescein angiography in the eye and a glomerular albumin permeability assay in the kidney. A type 2 diabetic (T2D, db/db) mouse model was used to determine the therapeutic potential of preventing heparan sulphate damage using treatment with a novel heparanase inhibitor, OVZ/HS-1638. Endothelial glycocalyx changes were measured as above, and microvascular barrier function assessed by albumin extravasation in the eye and a glomerular permeability assay in the kidney. RESULTS: In both models of heparan sulphate depletion, endothelial glycocalyx depth was reduced and retinal solute flux and glomerular albumin permeability was increased. T2D mice treated with OVZ/HS-1638 had improved endothelial glycocalyx measurements compared to vehicle treated T2D mice and were simultaneously protected from microvascular permeability changes associated with DR and DKD. CONCLUSION: We demonstrate that endothelial glycocalyx heparan sulphate plays a common mechanistic role in microvascular barrier function in the eye and kidney. Protecting the endothelial glycocalyx damage in diabetes, using the novel heparanase inhibitor OVZ/HS-1638, effectively prevents microvascular permeability changes associated with DR and DKD, demonstrating a novel systemic approach to address diabetic microvascular complications.


Assuntos
Diabetes Mellitus Tipo 2 , Angiopatias Diabéticas , Nefropatias Diabéticas , Glucuronidase , Animais , Camundongos , Glicocálix/metabolismo , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/prevenção & controle , Heparitina Sulfato/metabolismo , Heparitina Sulfato/farmacologia , Albuminas/farmacologia , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/prevenção & controle , Angiopatias Diabéticas/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo
17.
Clin Med (Lond) ; 24(2): 100031, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38369127

RESUMO

Diabetic retinopathy and nephropathy share pathophysiological mechanisms and there is a defined correlation between the severity of both these microvascular complications from suboptimal glycaemic control. The reno-protective properties offered by sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists should be applicable to diabetic retinopathy as well. However, in patients with pre-existing diabetic retinopathy, sudden improvement in glycaemic control is well documented to cause early worsening of the changes in the retina that is usually transient. This paradoxical phenomenon tends to occur with longer duration of diabetes, higher HbA1c at the outset, rapid improvement of glucose levels and the magnitude of HbA1c reduction with addition of more agents to tighten metabolic control. Interestingly, this progression of pre-existing diabetic retinopathy is not quite observed with newer sodium-glucose co-transporter-2 inhibitors. This article discusses potential further areas of future research where mechanisms of renal protection can be translated to the retina.


Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Retinopatia Diabética , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Hipoglicemiantes/uso terapêutico
18.
Metab Syndr Relat Disord ; 22(3): 170-178, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38386800

RESUMO

Type 2 diabetes (T2D) is the leading cause of chronic kidney disease (CKD). In addition, the cardiovascular prevalence in diabetic patients is around 32.2%, with a two-fold increased mortality risk compared to those without diabetes. Recent investigations have shed light on the promising cardioprotective and nephroprotective benefits of sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and nonsteroidal mineralocorticoid receptor antagonists (nsMRAs) for individuals with T2D. The evidence robustly indicates that SGLT2i and GLP-1RA significantly reduce the risk of CKD and cardiovascular disease (CVD), all while effectively managing blood glucose levels. Furthermore, combining SGLT2i with nsMRAs amplifies the benefits, potentially offering a more profound reduction in cardiovascular and renal outcomes. The data analysis strongly supports the integration of these pharmacological agents in the management strategies for CKD and CVD prevention among T2D patients, highlighting the importance of awareness among nephrologists, especially in regions with limited healthcare resources.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Insuficiência Renal Crônica , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Hipoglicemiantes/uso terapêutico , Rim/efeitos dos fármacos , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Nefropatias/etiologia , Nefropatias/prevenção & controle , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle
19.
J Diabetes Complications ; 38(2): 108652, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38190779

RESUMO

BACKGROUND: Diabetic kidney disease (DKD) is a secondary complication of diabetes mellitus and a leading cause of chronic kidney disease. AIM: To investigate the impact of long-term canagliflozin treatment on DKD and elucidate its underlying mechanism. METHODS: DKD model was established using high-fat diet and streptozotocin in male C57BL/6J mice (n = 30). Mice were divided into five groups and treated for 12 weeks. 1) normal control mice, 2) DKD model, 3) mice treated low-dose of canagliflozin, 4) high-dose of canagliflozin and 5) ß-hydroxybutyrate. Mice kidney morphology and function were evaluated, and a metabolomics analysis was performed. RESULTS: Canagliflozin treatment reduced blood creatinine and urine nitrogen levels and improved systemic insulin sensitivity and glucose tolerance in diabetic mice. Additionally, a decrease in histological lesions including collagen and lipid deposition in the kidneys was observed. ß-hydroxybutyrate treatment did not yield a comparable outcome. The metabolomics analysis revealed that canagliflozin induced alterations in amino acid metabolism profiles in the renal tissue of diabetic mice. CONCLUSION: Canagliflozin protects the kidneys of diabetic mice by increasing the levels of essential amino acids, promoting mitochondrial homeostasis, mitigating oxidative stress, and stimulating the amino acid-dependent tricarboxylic acid cycle.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Masculino , Camundongos , Ácido 3-Hidroxibutírico/uso terapêutico , Aminoácidos , Canagliflozina/farmacologia , Canagliflozina/uso terapêutico , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Nefropatias Diabéticas/etiologia , Rim/patologia , Camundongos Endogâmicos C57BL , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
20.
J Diabetes Complications ; 38(2): 108687, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38266571

RESUMO

AIMS: Diabetic nephropathy (DN) complicates diabetes Mellitus and intimately relates to intrarenal renin-angiotensin system (RAS) activity. Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), has been validated to improve renal outcomes in diabetic patients from clinical research by elusive mechanisms. This study explored the presumption that the eagerness activity of intrarenal RAS in DN generated oxidative stress to promote renal fibrosis, and the process can be interrupted by dapagliflozin. METHODS: A streptozotocin-induced DN model was established in male C57BL/6J mice. Mice were treated with dapagliflozin or losartan for 14 weeks. Biochemical data, renal fibrosis, oxidative stress, and RAS were measured. RESULTS: DN mice were characterized by overtly low body weight, high levels of blood glucose, and renal injury. Interrupting SGLT2 and RAS significantly improved renal dysfunction and pathological lesions in DN mice. Consistent with these favorable effects, dapagliflozin revoked the local RAS/oxidative stress and the succeeding transforming growth factor beta (TGFß) signaling. CONCLUSIONS: This research clarifies that intrarenal RAS activity triggers renal injury in DN, and dapagliflozin attenuates renal fibrosis by suppressing Angiotensin II/TGFß signaling. It unravels a novel insight into the role of prevention and treatment of SGLT2 inhibitors to DN.


Assuntos
Compostos Benzidrílicos , Diabetes Mellitus Experimental , Nefropatias Diabéticas , Glucosídeos , Humanos , Masculino , Camundongos , Animais , Angiotensina II , Transportador 2 de Glucose-Sódio/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Fator de Crescimento Transformador beta , Camundongos Endogâmicos C57BL , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Nefropatias Diabéticas/metabolismo , Rim/patologia , Fibrose
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