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1.
Life Sci ; 235: 116796, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31470003

RESUMO

AIM: Depressor arm of the renin-angiotensin system (RAS) exerts reno-protective effects in chronic kidney diseases like diabetic nephropathy. However, same is still elusive under AKI and hyperglycaemia comorbidity. Hence, the present study delineates the role of angiotensin-II type 2 receptor (AT2R) and angiotensin-converting enzyme 2 (ACE2) in AKI under normal and hyperglycaemia condition. METHODS: Non-diabetic (ND) and Streptozotocin-induced diabetes mellitus (DM) rats were subjected to ischemic renal injury (IRI). Rats underwent IRI were treated with an AT2R agonist, C21 (0.3 mg/kg/day, i.p.) or ACE2 activator, Dize, (5 mg/kg/day, p.o.) either alone or as combination therapy. Renal histopathology and immunohistochemistry, proximal tubular fraction isolation, ELISA, immunoblotting and qRT-PCR were performed for subsequent analysis. KEY FINDINGS: Rats subjected to IRI displayed an increase in plasma ACE, AT1R, AT2R, Ang II, and reduction in ACE2, Ang-(1-7) expressions, with augmented renal inflammation and apoptosis. These changes were more prominent in diabetic rats with IRI. Co-administration of C21 and Dize augmented ACE2, Ang-(1-7), AT2R and MasR expressions, and attenuated tubular injury in both DM and ND rats. CONCLUSION: We demonstrated that pharmacological activation of AT2R and ACE2 protects DM and ND rats from IRI by preventing oxidative stress, inflammation and apoptosis-mediated tubular damage.


Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Nefropatias Diabéticas/etiologia , Peptidil Dipeptidase A/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Animais , Apoptose , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Estresse Oxidativo , Peptidil Dipeptidase A/química , Ratos , Ratos Wistar , Receptor Tipo 2 de Angiotensina/química
2.
Pharmacol Rep ; 71(5): 958-967, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31470292

RESUMO

BACKGROUND: Neprilysin inhibitors (NEPi) are assisting the renin-angiotensin system (RAS) inhibitors in halting diabetic cardiomyopathy (DCM). Away from conventional tactic, a recent report revealed the renoprotective potential of NEPi and angiotensin-converting enzyme (ACE2) activator combination therapy against diabetic nephropathy. However, this combination so far not evaluated against DCM, thus the present investigation aiming the same. METHODS: Streptozotocin-induced (55 mg/kg, ip) type 1 diabetic (T1D) male Wistar rats were treated with either monotherapy of thiorphan (0.1 mg/kg/day, po) or diminazene aceturate (5 mg/kg/day, po), or their combination therapy, for four weeks. After hemodynamic measurements, all the rats' heart and plasma were collected for biochemistry, ELISA, histopathology, and immunoblotting. RESULTS: Metabolic perturbations and failing cardiac functions associated with diabetes were markedly attenuated by combination therapy. Besides, unfavourable alterations in RAS and natriuretic peptides system (NPS) were corrected by combination therapy. Interestingly, combination therapy significantly increased plasma and heart cGMP levels compared to T1D and monotherapy receiving rats. Moreover, rats receiving combination therapy exhibited significant inhibition of activated NF-κB, TGF-ß and apoptotic signalling, and a notable reduction in cardiac fibrosis when compared to T1D rats. Expressions of posttranslational histone modifications markers; H3K4Me2 and its methyltransferases (SET7/9 and RBBP5) were significantly enhanced in T1D hearts, which were significantly reduced by combination therapy. CONCLUSIONS: The NEPi and ACE2 activator combination therapy effectively prevented DCM by normalising RAS and NPS activities, increasing cGMP, inhibiting inflammatory, pro-fibrotic and apoptotic signalling, and reversing H3K4Me2 and its methyl transferases expressions.

3.
Life Sci ; 221: 159-167, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30769114

RESUMO

AIMS: Renin-angiotensin system (RAS) and natriuretic peptides system (NPS) perturbations govern the development of diabetic nephropathy (DN). Hence, in search of a novel therapy against DN, present study targeted both, NPS and RAS simultaneously using a neprilysin inhibitor (NEPi) in combination with either angiotensin receptor blocker (ARB) or angiotensin-converting enzyme 2 (ACE2) activator. METHODS: We induced diabetes in male Wistar rats by a single dose of streptozotocin (55 mg/kg, i.p.). After four weeks, we treated diabetic rats with thiorphan, telmisartan or diminazene aceturate (Dize) 0.1, 10, 5 mg/kg/day, p.o. alone as monotherapy, or both thiorphan/telmisartan or thiorphan/Dize as combination therapy, for four weeks. Then, plasma and urine biochemistry were performed, and kidneys from all the groups were collected and processed separately for histopathology, ELISA and Western blotting. KEY FINDINGS: Proposed combination therapies attenuated metabolic perturbations, prevented renal functional decline, and normalised adverse alterations in renal ACE, ACE2, Ang-II, Ang-(1-7), neprilysin and cGMP levels in diabetic rats. Histopathological evaluation revealed a significant reduction in glomerular and tubulointerstitial fibrosis by combination therapies. Importantly, combination therapies inhibited inflammatory, profibrotic and apoptotic signalling, way better than respective monotherapies, in preventing DN. CONCLUSION: Renoprotective potential of thiorphan (NEPi)/telmisartan (ARB) and thiorphan/Dize (ACE2 activator) combination therapies against the development of DN is primarily attributed to normalisation of RAS and NPS components and inhibition of pathological signalling related to inflammation, fibrosis, and apoptosis. Hence, we can conclude that NEPi/ARB and NEPi/ACE2 activator combination therapies might be new therapeutic strategies in preventing DN.


Assuntos
Nefropatias Diabéticas/metabolismo , Neprilisina/metabolismo , Sistema Renina-Angiotensina/fisiologia , Animais , Apoptose , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/prevenção & controle , Diminazena/análogos & derivados , Diminazena/metabolismo , Diminazena/farmacologia , Fibrose , Inflamação , Rim/patologia , Masculino , Neprilisina/antagonistas & inibidores , Peptidil Dipeptidase A , Ratos , Ratos Wistar , Sistema Renina-Angiotensina/efeitos dos fármacos , Estreptozocina , Telmisartan/metabolismo , Telmisartan/farmacologia , Tiorfano/metabolismo , Tiorfano/farmacologia
4.
Cardiovasc Res ; 115(2): 373-384, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30184174

RESUMO

Aims: LCZ696, a first-generation dual angiotensin receptor-neprilysin inhibitor (ARNi), is effective in treating heart failure patients. However, the role of ARNis in treating diabetic cardiomyopathy is poorly understood. This study evaluates the efficacy of a novel combination of telmisartan [angiotensin receptor blocker (ARB)] and thiorphan [neprilysin inhibitor (NEPi)] in ameliorating diabetic cardiomyopathy while, at the same time, exploring the relevant underlying molecular mechanism(s). Methods and results: Diabetes was induced by administration of streptozotocin (55 mg/kg, i.p.) in male Wistar rats. After 4 weeks, diabetic rats were subjected to either thiorphan (0.1 mg/kg/day, p.o.) or telmisartan (10 mg/kg/day, p.o.) monotherapy, or their combination, for a period of 4 weeks. Metabolic and morphometric alterations, failing ventricular functions, and diminished baroreflex indicated development of diabetic cardiac complications. Apart from morphometric alterations, all pathological consequences were prevented by telmisartan and thiorphan combination therapy. Diabetic rats exhibited significant modulation of the natriuretic peptide system, a key haemodynamic regulator; this was normalized by combination therapy. Histopathological studies showed augmented myocardial fibrosis, demonstrated by increased % PSR-positive area, with combination therapy giving the best improvement in these indices. More importantly, the combination of thiorphan and telmisartan was superior in attenuating inflammatory (NF-κB/MCP-1), profibrotic (TGF-ß/Smad7) and apoptotic (PARP/Caspase-3) cascades compared to respective monotherapies when treating rats with diabetic cardiomyopathy. In addition, diabetic heart chromatin was in a state of active transcription, indicated by increased histone acetylation (H2AK5Ac, H2BK5Ac, H3K9Ac, and H4K8Ac) and histone acetyltransferase (PCAF and Ac-CBP) levels. Interestingly, combination treatment was sufficiently potent to normalize these alterations. Conclusion: The protective effect of novel ARB and NEPi combination against diabetic cardiomyopathy can be attributed to inhibition of inflammatory, profibrotic, and apoptotic cascades. Moreover, reversal of histone acetylation assists its protective effect.

5.
Curr Mol Pharmacol ; 12(1): 61-71, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30465518

RESUMO

BACKGROUND: Natriuretic peptide system (NPS) alterations are involved in pathogenesis of diabetic cardiomyopathy (DCM) and nephropathy (DN), however its epigenetic regulation is still unclear. Interestingly, histone acetylation epigenetically regulates neprilysin expression in Alzheimer's disease. OBJECTIVES: The present study was aimed at delineating role of histone acetylation in regulation of NPS in DCM and DN. METHODS: Streptozotocin (55 mg/kg, i.p.)-induced diabetic male Wistar rats were used to mimic pathogenesis of DCM and DN. After haemodynamic measurements, all the rat's plasma, heart and kidney were collected for biochemistry, ELISA, protein isolation and western blotting, RT-PCR and chromatin immunoprecipitation (ChIP) assay. RESULTS: Diabetic rats heart and kidney exhibited activation of NF-κB and TGF-ß signalling with increased histone acetyl transferases (PCAF/CBP) expressions and augmented H2AK5Ac, H2BK5Ac, H3K18Ac, and H4K8Ac levels. ChIP assay results showed increased enrichment of H3K18Ac and H2BK5Ac at Nppa, Nppb (Heart) and Mme promoter (Heart/Kidney) in diabetic rats. Enrichment of H2AK5Ac was augmented on Nppa and Mme promoters in diabetic heart, while it remained unchanged on Nppb promoter in heart and Mme promoter in kidney. CONCLUSION: Augmented histone acetylation at promoter regions of NPS gene(s), at least in a part, is responsible for increased expressions of ANP, BNP and NEP in diabetic heart and kidney. Hence, histone acetylation inhibitors can be considered as novel therapeutic targets against DCM and DN.


Assuntos
Cardiomiopatias Diabéticas/patologia , Nefropatias Diabéticas/patologia , Histonas/metabolismo , Peptídeos Natriuréticos/metabolismo , Neprilisina/metabolismo , Acetilação , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Cardiomiopatias Diabéticas/metabolismo , Nefropatias Diabéticas/metabolismo , Expressão Gênica , Hemodinâmica , Histona Acetiltransferases/genética , Histona Acetiltransferases/metabolismo , Rim/metabolismo , Masculino , Miocárdio/metabolismo , NF-kappa B/metabolismo , Peptídeos Natriuréticos/genética , Neprilisina/genética , Regiões Promotoras Genéticas , Ratos , Ratos Wistar , Receptores do Fator Natriurético Atrial/genética , Transdução de Sinais
6.
Pharmacol Rep ; 71(5): 958-967, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31994035

RESUMO

BACKGROUND: Neprilysin inhibitors (NEPi) are assisting the renin-angiotensin system (RAS) inhibitors in halting diabetic cardiomyopathy (DCM). Away from conventional tactic, a recent report revealed the renoprotective potential of NEPi and angiotensin-converting enzyme (ACE2) activator combination therapy against diabetic nephropathy. However, this combination so far not evaluated against DCM, thus the present investigation aiming the same. METHODS: Streptozotocin-induced (55 mg/kg, ip) type 1 diabetic (T1 D) male Wistar rats were treated with either monotherapy of thiorphan (0.1 mg/kg/day, po) or diminazene aceturate (5 mg/kg/day, po), or their combination therapy, for four weeks. After hemodynamic measurements, all the rats' heart and plasma were collected for biochemistry, ELISA, histopathology, and immunoblotting. RESULTS: Metabolic perturbations and failing cardiac functions associated with diabetes were markedly attenuated by combination therapy. Besides, unfavourable alterations in RAS and natriuretic peptides system (NPS) were corrected by combination therapy. Interestingly, combination therapy significantly increased plasma and heart cGMP levels compared to T1D and monotherapy receiving rats. Moreover, rats receiving combination therapy exhibited significant inhibition of activated NF-KB, TGF-p and apoptotic signalling, and a notable reduction in cardiac fibrosis when compared to Tl D rats. Expressions of posttranslational histone modifications markers; H3K4Me2 and its methyltransferases (SET7/9 and RBBP5) were significantly enhanced in T1D hearts, which were significantly reduced by combination therapy. CONCLUSIONS: The NEPi and ACE2 activator combination therapy effectively prevented DCM by normalising RAS and NPS activities, increasing cGMP, inhibiting inflammatory, pro-fibrotic and apoptotic signalling, and reversing H3K4Me2 and its methyl transferases expressions.

7.
Biomed Pharmacother ; 95: 1461-1468, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28946194

RESUMO

Micro and macro vascular complications under diabetic condition are the responses to pathological stimuli exerted by up regulated renin angiotensin system (RAS) via deteriorating vascular physiology. Up-regulated RAS could influence in the adaptive mechanisms of target tissues to alter the abundance of angiotensin II type 1 receptor (AT1) and angiotensin II type 2 receptor (AT2). Such differential regulation of AT1 and AT2 have been reported to be associated with post-translational histone modifications (PTHMs). Additionally, recent evidences provide, esculetin (6,7-dihydroxycoumarin) reverses post-translational histone modifications (PTHMs) in diabetic cardiomyopathy and nephropathy. On account of these evidences, we further pursued this study to investigate the effects of esculetin on PTHMs in progressive vascular complications under insulin resistance (IR) and type 2 diabetic (T2D) conditions. Esculetin treatment in both IR and T2D conditions substantially improved vascular reactivity, increased eNos and decreased Vcam1 mRNA levels, and reduced collagen deposition in rat thoracic aorta. Further, the fold changes in At1 and At2 receptor mRNA in IR and T2D were reversed by esculetin treatment. Modifications in histone H2B lysine 120 monoubiquitination (H2BK120Ub) were also reversed in esculetin treatment group. Further, modification in the occupancy of H2BK120Ub at At1a, At2, Tgfß and Mcp1 promoter genes was evidenced by treatment with esculetin. Taken together, our investigation concluded with the involvement of esculetin in the amelioration of vascular perturbation by modifying H2BK120Ub along with occupancy at At1, At2, Tgfß1 and Mcp1 promoter gene.


Assuntos
Vasos Sanguíneos/patologia , Quimiocina CCL2/genética , Diabetes Mellitus Tipo 2/genética , Histonas/metabolismo , Regiões Promotoras Genéticas/genética , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/genética , Fator de Crescimento Transformador beta1/genética , Umbeliferonas/farmacologia , Acetilcolina/farmacologia , Angiotensina II/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Resistência à Insulina/genética , Lisina/metabolismo , Relaxamento Muscular/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ubiquitina/metabolismo , Umbeliferonas/química
8.
Br J Pharmacol ; 174(18): 3118-3130, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28688122

RESUMO

BACKGROUND AND PURPOSE: One of the protective actions of angiotensin converting enzyme-2 (ACE2) is the inactivation of angiotensin II. Expression and activity of ACE2 was reduced in glomeruli of diabetic patients and in animal models of diabetes. Recently the potential role of recombinant ACE2 administration in preventing diabetic nephropathy (DN) has been shown. Here we have tested the effects of the ACE2 activator, diminazene aceturate (DIZE), in a model of DN. EXPERIMENTAL APPROACH: Male Wistar rats were rendered diabetic using a single dose of streptozotocin (55 mg·kg-1 , i.p.). After 4 weeks, diabetic animals were divided into experimental groups and treated with DIZE, at a low dose (5 mg·kg-1 ·day-1 ), a high dose (15 mg·kg-1 ·day-1 ) and the high dose with of the AT2 receptor antagonist PD123319 (10 mg·kg-1 ·day-1 ). At the end of the treatment , kidneys from all the groups were collected and processed separately for glomerular isolation, protein isolation, mRNA extraction and for immunohistochemical studies. KEY RESULTS: Treatment with DIZE restored ACE2 expression in glomeruli and increased expression of AT2 receptors in whole kidney and isolated glomeruli of diabetic animals. DIZE administration reduced angiotensin II levels and increased angiotensin-(1-7) levels in diabetic kidney. However, PD123319 treatment reversed all these actions of DIZE. CONCLUSIONS AND IMPLICATIONS: DIZE treatment reduced diabetes-induced renal damage as shown by reduction of fibrosis and apoptosis. These protective actions of DIZE were blocked by the AT2 receptor antagonist. Taken together, these results suggest that DIZE protected against DN through the ACE2/angiotensin-(1-7)/ AT2 receptor axis.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Diminazena/análogos & derivados , Modelos Animais de Doenças , Peptidil Dipeptidase A/biossíntese , Receptor Tipo 2 de Angiotensina/biossíntese , Animais , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/metabolismo , Nefropatias Diabéticas/metabolismo , Diminazena/administração & dosagem , Diminazena/antagonistas & inibidores , Diminazena/farmacologia , Relação Dose-Resposta a Droga , Imidazóis/farmacologia , Masculino , Piridinas/farmacologia , Ratos , Ratos Wistar , Estreptozocina , Relação Estrutura-Atividade
9.
Pharmacol Rep ; 69(4): 666-672, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28527877

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD), a chronic metabolic disorder is associated with oxidative stress, inflammation and fibrotic cascades. In this study, we aimed to examine the effects of Esculetin, a well-known anti-oxidant on TGF-ß1 mediated liver fibrosis and FoxO1 activity. METHODS: A non-genetic murine model for NAFLD was developed by chronic high fat diet (HFD) (58% calories from fats) feeding in Wistar rats. The plasma biochemical parameters, liver function tests, oxidative stress, and histopathological alterations were assessed. The alterations in extracellular matrix (ECM) deposition and FoxO1 activity were assessed by immunohistochemistry. RESULTS: The aberrations in plasma parameters, liver functioning, morphometric and microscopic changes in liver structure of HFD fed rats were significantly improved by treatment with Esculetin. Liver fibrosis, identified in the form of collagen deposition and expression of fibrotic proteins like TGF-ß1 and fibronectin was also markedly controlled by Esculetin. The expression of phospho-FoxO1 was found to be reduced in HFD fed rats' liver, showing an increase in activation of FoxO1 under insulin resistant and hyperglycemic states. Esculetin treatment could improve phospho-FoxO1 expression, thus showing its ability to act on Akt/PI3K/FoxO1 pathway. CONCLUSIONS: As per the previous studies, a potential therapy for NAFLD may be the one with multi-faceted actions on insulin resistance, oxidative stress, inflammation and fibrosis. This study demonstrates the efficiency of Esculetin in improving liver fibrosis in HFD induced NAFLD.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Proteínas do Tecido Nervoso/metabolismo , Hepatopatia Gordurosa não Alcoólica/complicações , Umbeliferonas/farmacologia , Animais , Masculino , Proteínas do Tecido Nervoso/genética , Hepatopatia Gordurosa não Alcoólica/etiologia , Ratos , Ratos Wistar
10.
Biomed Pharmacother ; 90: 752-759, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28419972

RESUMO

Diabetes is an enormous and ever-growing calamity and a global public health threat of the 21st century. Besides insulin and oral hypoglycaemic drugs, blockage of the renin-angiotensin system (RAS) denotes a key pharmacotherapy for the management of cardiovascular (CVD) and chronic kidney diseases (CKD), which are the leading causes of disability and death among diabetic patients. Neprilysin (NEP) inhibition, auxiliary to RAS blockage increases the bioavailability of natriuretic peptides and benefits the cardio-renal system. Omapatrilat, a dual angiotensin-converting enzyme (ACE) and NEP inhibitor has been reported to show superior anti-hypertensive, anti-atherosclerotic, insulin-sensitizing, cardiovascular and renoprotective effects to ACE inhibitors in experimental animal models for diabetes. In clinical trials on hypertensive subjects Omapatrilat increased the risk of angioedema due to which its further development as anti-hypertensive drug was hampered. This event prompted the development of angiotensin receptor neprilysin inhibitors (ARNi). The first representative of ARNi, LCZ696 (Sacubitril/ Valsartan) halted cardiovascular and renal functional decline and hence protected against CKD and CVD. Recently, LCZ696 was approved by U.S. Food and Drug Administration for the treatment of heart failure. This concise review intends to summarise the currently available reports on NEPi as a therapeutic intervention to treat CVD and CKD associated with diabetes.


Assuntos
Aminobutiratos/farmacologia , Aminobutiratos/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Complicações do Diabetes/tratamento farmacológico , Neprilisina/antagonistas & inibidores , Insuficiência Renal Crônica/tratamento farmacológico , Tetrazóis/farmacologia , Tetrazóis/uso terapêutico , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Doenças Cardiovasculares/etiologia , Diabetes Mellitus , Humanos , Insuficiência Renal Crônica/etiologia
11.
Indian J Pharmacol ; 49(5): 348-356, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29515275

RESUMO

OBJECTIVES: Although cardioprotective effects of telmisartan are well explored, its effects on epigenetic alterations associated with type 2 diabetic (T2D) cardiomyopathy remain unmapped. Thus, the present study was designed to evaluate the potential of esculetin and telmisartan combination to reverse histone posttranslational modifications (PTMs) in curbing T2D cardiomyopathy. MATERIALS AND METHODS: T2D was induced by high-fat diet feeding along with low dose of streptozotocin (35 mg/kg, I.P) in male Wistar rats. T2D rats were treated with either telmisartan (10 mg/kg/day, P.O) or esculetin (50 mg/kg/day doses, P.O) or their combination for 2 weeks. Biochemical estimations, vascular reactivity, immunohistochemistry, and western blotting experiments were performed to evaluate the effects of the treatment in T2D cardiomyopathy. RESULTS: Esculetin and telmisartan combination alleviated the pathological features of T2D cardiomyopathy including metabolic perturbations, morphometric alterations, altered vascular reactivity, increased Keap1 and fibronectin expression more effectively than their respective monotherapy. This is the first report showing that telmisartan attenuates increased level of histone PTMs such as H3K9me2, H3K9Ac, H2AK119Ub, and H2BK120Ub in heart of T2D rats. The combination regimen showed a more significant reduction in augmented histone PTMs associated with T2D cardiomyopathy than their independent treatments. CONCLUSIONS: The present study demonstrates that esculetin and telmisartan combination can be an advanced pharmacological approach to ameliorate T2D cardiomyopathy which could be partially attributed to its ability to reverse the epigenetic alterations.


Assuntos
Benzimidazóis/farmacologia , Benzoatos/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cardiomiopatias Diabéticas/tratamento farmacológico , Umbeliferonas/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Benzimidazóis/administração & dosagem , Benzoatos/administração & dosagem , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Quimioterapia Combinada , Código das Histonas/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Estreptozocina , Telmisartan , Umbeliferonas/administração & dosagem
12.
Biochimie ; 131: 68-76, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27693081

RESUMO

Monocyte chemoattractant protein (MCP-1) and transforming growth factor-ß (TGF-ß1)-markers of inflammation and fibrosis, are central to type 2 diabetic nephropathy (T2DN) progression. The epigenetic basis of their expression has also been explored to certain extent. H2A lysine 119 monoubiquitination (H2AK119Ub), a repressive chromatin mark regulates progression of hyperglycaemia induced fibrosis in glomerular mesangial cells. However, how H2AK119Ub affects the expression of MCP-1 and TGF-ß1 and their regulation by Angiotensin II receptor subtypes remains unknown. In the current study, we aimed to study the effect of Angiotensin II receptors' blockade on the macrophage infiltration and histone modifications occurring at the promoter region of Mcp1 and Tgfb1in high fat diet fed and low dose streptozotocin treated male Wistar rats. Hereby, we present the first report delineating a distinct link between H2AK119Ub and macrophage infiltration and fibrosis i.e. the enrichment of H2AUb at Mcp1 and Tgfb1 promoter region was found to reduce drastically in the T2DN which could be significantly reversed by Telmisartan and was further elevated by PD123319. We could conclude that the Angiotensin II mediated macrophage infiltration in T2DN is regulated at least partially by H2AK119Ub through both AT1 and AT2 receptors, which to the best of our knowledge, presents the first report for the regulation of Mcp1 by H2AK119Ub. Thus an approach targeting AT1R blockade and AT2R activation accompanied by an epigenetic modulator may be more suitable to ameliorate the macrophage infiltration and fibrosis associated with T2DN.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/metabolismo , Histonas/metabolismo , Macrófagos/metabolismo , Receptores de Angiotensina/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 2 de Angiotensina II/farmacologia , Animais , Benzimidazóis/farmacologia , Benzoatos/farmacologia , Western Blotting , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/genética , Fibrose , Imidazóis/farmacologia , Rim/metabolismo , Rim/patologia , Lisina/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Masculino , Regiões Promotoras Genéticas/genética , Piridinas/farmacologia , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Telmisartan , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Ubiquitinação/efeitos dos fármacos
13.
Biochem J ; 473(21): 3937-3949, 2016 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-27582499

RESUMO

Hyperglycaemia-induced expression of extracellular matrix (ECM) components plays a major role in the development of diabetic nephropathy (DN). The epigenetic mechanisms that modulate ECM gene expression in DN remain unclear. Therefore, we examined the role of histone H2A and H2B monoubiquitination on epigenetic chromatin marks, such as histone H3 lysine dimethylation (H3K4Me2, H3K9Me2 and H3K79Me2) in type 1 diabetic rat kidney. Hyperglycaemia increased collagen deposition and Col1a1 gene expression. In whole kidney of diabetic animals, both H2AK119 mono-ubiquitination (H2AK119Ub) and H2BK120 mono-ubiquitination (H2BK120Ub) were found to be increased, whereas, in glomeruli of diabetic animals, expression of both H2AK119Ub and H2BK120Ub was reduced. Changes in ubiquitin proteasome system components like increased Rnf2 (H2A-specific E3 ligase) and decreased H2A- and H2B-specific deubiquitinases (ubiquitin-specific proteases 7, 16, 21 and 22) were also observed. Globally increased levels of chromatin marks associated with active genes (H3K4Me2 and H3K79Me2) and decreased levels of repressive marks (H3K9Me2) were also observed. Hyperglycaemia also increased the protein expression of SET7/9 and decreased the expression of SUV39H1. We also showed the decreased occupancy of H2AK119Ub and H2BK120Ub on the promoters of Set7/9 and Suv39h1 in diabetic kidney. In addition, methylation marks regulated by H2AK119Ub (H3K27Me2 and H3K36Me2) and H2BK120Ub (H3K4Me2 and H3K79Me2) were also found to be altered on the promoters of Set7/9 and Suv39h1 Taken together, these results show the functional role of H2AK119Ub and H2BK120Ub in regulating histone H3K4Me2 and H3K9Me2 through modulating the expression of SET7/9 and SUV39H1 in the development of diabetic renal fibrosis.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Rim/metabolismo , Animais , Western Blotting , Imunoprecipitação da Cromatina , Colágeno/metabolismo , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Epigênese Genética/genética , Glomérulos Renais/metabolismo , Masculino , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Ubiquitinação/fisiologia
14.
Toxicol Appl Pharmacol ; 306: 17-26, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27343405

RESUMO

Angiotensin-I converting enzyme (ACE) is positively correlated to asthma, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS) and is highly expressed in lungs. ACE2, the counteracting enzyme of ACE, was proven to be protective in pulmonary, cardiovascular diseases. In the present study we checked the effect of ACE2 activation in animal model of asthma. Asthma was induced in male wistar rats by sensitization and challenge with ovalbumin and then treated with ACE2 activator, diminazene aceturate (DIZE) for 2weeks. 48h after last allergen challenge, animals were anesthetized, blood, BALF, femoral bone marrow lavage were collected for leucocyte count; trachea for measuring airway responsiveness to carbachol; lungs and heart were isolated for histological studies and western blotting. In our animal model, the characteristic features of asthma such as altered airway responsiveness to carbachol, eosinophilia and neutrophilia were observed. Western blotting revealed the increased pulmonary expression of ACE1, IL-1ß, IL-4, NF-κB, BCL2, p-AKT, p-p38 and decreased expression of ACE2 and IκB. DIZE treatment prevented these alterations. Intraalveolar interstitial thickening, inflammatory cell infiltration, interstitial fibrosis, oxidative stress and right ventricular hypertrophy in asthma control animals were also reversed by DIZE treatment. Activation of ACE2 by DIZE conferred protection against asthma as evident from biochemical, functional, histological and molecular parameters. To the best of our knowledge, we report for the first time that activation of ACE2 by DIZE prevents asthma progression by altering AKT, p38, NF-κB and other inflammatory markers.


Assuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Diminazena/análogos & derivados , Peptidil Dipeptidase A/metabolismo , Animais , Antiasmáticos/farmacologia , Asma/metabolismo , Asma/patologia , Asma/fisiopatologia , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Diminazena/farmacologia , Diminazena/uso terapêutico , Modelos Animais de Doenças , Glutationa/metabolismo , Proteínas I-kappa B/metabolismo , Interleucina-1beta/metabolismo , Interleucina-4/sangue , Interleucina-4/metabolismo , Contagem de Leucócitos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Malondialdeído/metabolismo , Miocárdio/patologia , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Ovalbumina , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Wistar , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
15.
Curr Diabetes Rev ; 12(3): 223-30, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26239835

RESUMO

FoxO1, one of the most widely expressed sub-families of the winged helix forkhead factors, is biologically 'omni-functional' owing to its far-flung roles in metabolism, cell cycle, tissue differentiation and development and oxidative stress response. The knowledge of involvement of FoxO1 in metabolic disorders has long been there, but the potential target remained underutilized due to unavailability of specific and potent inhibitors. The review provides an insight into the role of FoxO1 in orchestrating metabolic diseases' pathogenesis (including diabetes, its secondary complications and obesity) and compiles the literature on FoxO1 inhibitors. The emergence of various natural molecules and synthesized small molecules like AS1842856 as FoxO1 inhibitors urges us to think further and decide the future course of drug development for the management of metabolic disorders.


Assuntos
Proteína Forkhead Box O1/antagonistas & inibidores , Doenças Metabólicas/tratamento farmacológico , Quinolonas/farmacologia , Quinolonas/uso terapêutico , Terapias em Estudo/tendências , Animais , Complicações do Diabetes/tratamento farmacológico , Complicações do Diabetes/genética , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/genética , Proteína Forkhead Box O1/fisiologia , Humanos , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Obesidade/tratamento farmacológico , Obesidade/genética , Obesidade/metabolismo , Terapias em Estudo/métodos
16.
Eur J Pharmacol ; 765: 591-7, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26409041

RESUMO

The combination of the angiotensin receptor blockers (ARBs) with other synthetic and natural molecules has been reported to have better safety profile and therapeutic efficacy in prevention of diabetes and its associated complications than their monotherapy. Driven by the aforementioned facts, this study was conceived to evaluate the potential additive effect of combination of Telmisartan and Esculetin in prevention of insulin resistance and associated cardiac fibrosis. Recently, we have reported that Esculetin prevented cardiovascular dysfunction associated with insulin resistance (IR) and type 2 diabetes. Insulin resistance was developed by high fat diet (HFD) feeding to Wistar rats. Telmisartan and Esculetin were administered at 10 mg/kg/day and 50 mg/kg/day doses (P.O, 2 weeks), respectively either alone or in combination. Plasma biochemical analyses, vascular reactivity and immunohistochemical experiments were performed to assess the beneficial effect of Telmisartan, Esculetin and their combination on insulin resistance and associated cardiac fibrosis. The study results showed that, co-administered Telmisartan and Esculetin ameliorated the pathological features like metabolic perturbation, morphometric alterations, vascular hyper responsiveness, extracellular matrix accumulation and the expression of fibronectin and TGF-ß more effectively than monotherapy in HFD fed rats. Hence, the study urges us to conclude that the solution to IR and associated cardiovascular dysfunction may lie in the Telmisartan and Esculetin combination therapy.


Assuntos
Angiotensina II/toxicidade , Benzimidazóis/administração & dosagem , Benzoatos/administração & dosagem , Cardiotônicos/administração & dosagem , Cardiopatias/prevenção & controle , Resistência à Insulina/fisiologia , Umbeliferonas/administração & dosagem , Vasoconstrição/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Fibrose , Cardiopatias/induzido quimicamente , Cardiopatias/metabolismo , Masculino , Ratos , Ratos Wistar , Telmisartan , Resultado do Tratamento , Vasoconstrição/fisiologia
17.
Biochimie ; 118: 71-81, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26271886

RESUMO

Angiotensin II (Ang II) acts through Angiotensin Converting Enzyme (ACE)/Ang II type 1 receptor (AT1R) axis to promote renal failure whereas the Ang II type 2 receptor (AT2R)/Angiotensin Converting Enzyme 2 (ACE2)/Ang1-7/Mas axis constitutes the protective arm of Renin Angiotensin System (RAS). Though Ang II has been known to activate the Nuclear Factor-κB (NF-κB) signalling pathway through different receptor subtype(s) in different tissues under various diseases, the subtype orchestrating this stimulation in type 2 diabetic kidney remains elusive. ACE2, a protective monocarboxypeptidase, responsible for conversion of Ang II to Ang1-7, opposes the deleterious effects of RAS pathway but how its expression is altered with blockade of AT1R and AT2R is not yet known. Hence, the present study was conceived to understand the regulation of NF-κB and ACE2 by using specific AT1 and AT2 receptor antagonists in non-genetic model of type 2 diabetic nephropathy. Our results show that the AT1R and AT2R antagonists lead to the repression and activation of NF-κB signalling pathway, respectively which suggests the role of AT1R in NF-κB activation. The blockade of AT2R led to an increase in ACE2 expression, which may be a compensatory response to the drastically increased inflammatory mediators and oxidative stress in the diabetic kidney. To the best of our knowledge, this is the first study showing the differential regulation of NF-κB and ACE2 by Ang II receptor subtypes and thus this study improves our understanding regarding regulation of inflammatory cascade and ACE2 by AT1R and AT2R in type 2 diabetic kidney, which may help in designing novel strategies to combat the disease in future.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/metabolismo , NF-kappa B/metabolismo , Peptidil Dipeptidase A/metabolismo , Receptores de Angiotensina/metabolismo , Animais , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/patologia , Nefropatias Diabéticas/patologia , Modelos Animais de Doenças , Imuno-Histoquímica , Ratos , Ratos Wistar , Receptor Tipo 1 de Angiotensina/metabolismo , Transdução de Sinais/fisiologia
18.
CNS Neurol Disord Drug Targets ; 14(10): 1317-27, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26295811

RESUMO

The delivery of drugs to brain is a daunting task due to the presence of multiple protective barriers. Nanoparticles (NPs), due to their ability to deliver and accumulate drugs in brain by crossing the blood brain barrier, have emerged as effective brain targeting drug delivery system. The major drawback of NPs obstructing their application in brain related diseases is neurotoxicity which leads to memory deficit, behavioural changes, changes in the structure and membrane potential of the neurons. An understanding of the molecular mechanisms associated with nanoparticle induced neurotoxicity is essential to solve the problem. NPs induce cytotoxicity, genotoxicity and epigenetic changes. This review focuses on nanoparticles, their physicochemical characteristics, manifestations of neurotoxicity and the mechanisms through which neurotoxicity is induced. This review may help in improving the understanding of the mechanisms associated with nanoparticle induced neurotoxicity so as to devise ways to overcome the associated neurotoxicity.


Assuntos
Encéfalo/efeitos dos fármacos , Nanopartículas/toxicidade , Animais , Humanos
19.
Biochem Biophys Res Commun ; 461(2): 342-7, 2015 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-25887801

RESUMO

Esculetin (6, 7- dihydroxycoumarin) was found to be protective against hepatic and renal damage associated with Streptozotocin (STZ) induced type 1 diabetes, because of its radical scavenging property. However, there are no reports regarding its effect on vascular dysfunction under hyperinsulinemic and hyperglycemic conditions. Hence, the present study aimed to investigate the effect of esculetin on vascular dysfunction under these conditions. Non-genetic model of hyperinsulinemia and hyperglycemia were developed by high fat diet (HFD) feeding and HFD + Streptozotocin (STZ, 35 mg/kg, I.P) treatment in Wistar rats, respectively. Esculetin was administered at 50 and 100 mg/kg/day (P.O, 2 weeks) doses and biochemical, vascular reactivity and immunohistochemical experiments were performed to assess the effect of esculetin on vascular dysfunctions. Esculetin treatment significantly attenuates metabolic perturbations, alleviates insulin levels in hyperinsulinemic condition. Thoracic aorta of hyperinsulinemic and hyperglycemic rats showed hyper-responsiveness to Ang II mediated contraction and impaired acetylcholine mediated relaxation, and esculetin attenuates alterations in vascular reactivity to Ang II and acetylcholine challenges. In addition, immunohistochemical evaluations revealed that esculetin prevents increase in AT1R, AT2R, Keap1, TGF-ß, and decrease in ACE2 expression in aorta of hyperinsulinemic and hyperglycemic rats.


Assuntos
Acetilcolina/metabolismo , Angiotensina II/metabolismo , Diabetes Mellitus Experimental/complicações , Hiperglicemia/complicações , Hiperinsulinismo/complicações , Hipertensão/prevenção & controle , Umbeliferonas/uso terapêutico , Animais , Antioxidantes/uso terapêutico , Aorta/metabolismo , Aorta/patologia , Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Hiperinsulinismo/metabolismo , Hiperinsulinismo/patologia , Hipertensão/etiologia , Hipertensão/metabolismo , Hipertensão/patologia , Masculino , Peptidil Dipeptidase A/análise , Ratos Wistar , Fator de Crescimento Transformador beta/análise
20.
Biochem Pharmacol ; 93(3): 343-51, 2015 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-25482567

RESUMO

Growing body of evidence points out the crucial role of ACE2 in preventing atherosclerosis. However, data on how atherosclerosis affects ACE2 expression in heart and kidney remains unknown. Atherosclerosis was induced by feeding New Zealand White rabbits with high cholesterol diet (HCD - 2%) for 12 weeks and atorvastatin was administered (5mg/kg/day p.o) in last 3 weeks. ACE2 mRNA and protein expression was assessed by Western blotting and real time PCR. HCD fed rabbits developed atherosclerosis as confirmed by increase in plasma total cholesterol, LDL and triglycerides as well as formation atherosclerotic plaques in arch of aorta. The ACE2 protein but not mRNA expression was reduced in heart and kidney of HCD rabbits. Interestingly, atorvastatin increased the ACE2 protein expression in heart and kidney of HCD rabbits. However, atorvastatin increased ACE2 mRNA in heart but not in kidney of HCD rabbits. Atorvastatin increased the occupancy of histone H3 acetylation (H3-Ac) mark on ACE2 promoter region in heart of HCD rabbits indicating direct or indirect epigenetic up-regulation of ACE2 by atorvastatin. Further, atorvastatin suppressed Ang II-induced contractile responses and enhanced AT2 receptor mediated relaxant responses in atherosclerotic aorta. We propose that atherosclerosis is associated with reduced ACE2 expression in heart and kidney. We also show an unexplored potential of atorvastatin to up-regulate ACE2 via epigenetic histone modifications. Our data suggest a novel way of replenishing ACE2 expression for preventing not only atherosclerosis but also other cardiovascular disorders.


Assuntos
Aterosclerose/metabolismo , Modelos Animais de Doenças , Epigênese Genética/efeitos dos fármacos , Ácidos Heptanoicos/uso terapêutico , Histonas/biossíntese , Peptidil Dipeptidase A/biossíntese , Pirróis/uso terapêutico , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Atorvastatina , Epigênese Genética/fisiologia , Ácidos Heptanoicos/farmacologia , Histonas/genética , Masculino , Peptidil Dipeptidase A/genética , Pirróis/farmacologia , Coelhos , Distribuição Tecidual/efeitos dos fármacos , Distribuição Tecidual/fisiologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia
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