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Allisartan isoproxil attenuates oxidative stress and inflammation through the SIRT1/Nrf2/NF??B signalling pathway in diabetic cardiomyopathy rats.

ABSTRACT: Allisartan isoproxil is a new nonpeptide angiotensin II receptor blocker (ARB) precursor drug that is used to treat hypertension and reduce the risk of heart disease. The present study explored the effects of allisartan isoproxil on diabetic cardiomyopathy (DCM) and revealed the roles of hyperglycaemia?induced oxidative stress and inflammation. A rat DCM model was established by high?fat diet feeding in combination with intraperitoneal injection of streptozocin. Echocardiographs showed that diabetic rats exhibited significantly decreased cardiac function. Troponin T (cTnT) and B?type natriuretic peptide (BNP) were significantly increased in DCM rats as obtained by ELISA. Allisartan isoproxil significantly improved the EF% and E'/A' ratio. Histopathologic staining showed that allisartan isoproxil prevented histological alterations, attenuated the accumulation of collagen, and ameliorated cTnT and BNP levels. Western blot and immunohistochemical results indicated that the expression levels of silent information regulator 2 homologue 1 (SIRT1) and nuclear factor erythroid 2?related factor 2 (Nrf2) were decreased in the hearts of diabetic rats, and antioxidant defences were also decreased. In addition, allisartan isoproxil decreased the expression of NF??B p65 and the inflammatory cytokines TNF?? and IL?1? which were determined by reverse transcription?quantitative PCR in the diabetic heart. Western blotting and TUNEL staining results also showed that cardiac Bax and cleaved caspase?3 and the number of apoptotic myocardial cells were increased in the diabetic heart and decreased following treatment with allisartan isoproxil. In conclusion, the present results indicated that allisartan isoproxil alleviated DCM by attenuating diabetes?induced oxidative stress and inflammation through the SIRT1/Nrf2/NF??B signalling pathway.

SUBMITTER: Jin Q

PROVIDER: S-EPMC7845586 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Allisartan isoproxil attenuates oxidative stress and inflammation through the SIRT1/Nrf2/NF‑κB signalling pathway in diabetic cardiomyopathy rats.

Jin Qinyang Q Zhu Qin Q Wang Kai K Chen Mengli M Li Xinli X

Molecular medicine reports 20210126 3

Allisartan isoproxil is a new nonpeptide angiotensin II receptor blocker (ARB) precursor drug that is used to treat hypertension and reduce the risk of heart disease. The present study explored the effects of allisartan isoproxil on diabetic cardiomyopathy (DCM) and revealed the roles of hyperglycaemia‑induced oxidative stress and inflammation. A rat DCM model was established by high‑fat diet feeding in combination with intraperitoneal injection of streptozocin. Echocardiographs showed that diab ...[more]

PMID: 33495841

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Project description:BackgroundDiabetic nephropathy (DN) is among the most common microvascular complications of diabetes resulting in end-stage renal disease and therefore search for candidates which can ameliorate the kidney function is needed simultaneously with standard diabetic pharmacotherapy. The current study was aimed to investigate the effect of long term sacubitril/valsartan therapy (LCZ696) in diabetic rats to assess its ameliorative impact against various pathological parameters such as oxidative stress, inflammation and glomerulosclerosis associated with chronic DN.MethodsA single dose (60 mg/kg/day) of STZ was used to induce type 1 diabetes in adult male wistar rats. 2 weeks after diabetes induction, these rats were treated orally with valsartan (31 mg/kg) or LCZ696 (68 mg/kg) for 6 weeks. At end of the treatment period, serum and kidney samples were collected and analyzed. The serum levels of glucose, insulin, urea, creatinine, TNF-α, IL-1β, IL-6 and IL-10 levels were estimated. In renal tissue homogenate, the levels of inflammatory markers such as TNF-α, IL-1β, IL-6, NF-kB along with oxidative stress biomarkers including thiobarbituric acid-reacting substances (TBARs), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST) were assessed. Histological changes were observed in kidney.ResultsTime course therapy withLCZ696 and valsartan in diabetic rats resulted in significant reduction of serum glucose, urea and creatinine levels (P < 0.05). Additionally, serum of treated diabetic rats showed a diminution in inflammatory (TNF-α, IL-1β, IL-6) and increment in anti-inflammatory (IL-10) cytokines levels (P < 0.05). Tissue homogenate of the kidney extracted from LCZ696 and valsartan treated diabetic rats revealed a substantial reduction in the levels of inflammatory markers such as TNF-α, IL-1β, IL-6, NF-kB and sufficient restoration of anti-oxidant enzyme levels (P < 0.05). Finally, in the histological sections of the kidney, prevention of renal injury was observed with limited necrosis and inflammatory cells infiltration.ConclusionPresent data suggest that LCZ696 has sufficient therapeutic potential to restrict DN progression through inhibiting inflammation, oxidative stress and glomerulosclerosis.

Dataset Information

Allisartan isoproxil attenuates oxidative stress and inflammation through the SIRT1/Nrf2/NF??B signalling pathway in diabetic cardiomyopathy rats.

Publications

Allisartan isoproxil attenuates oxidative stress and inflammation through the SIRT1/Nrf2/NF‑κB signalling pathway in diabetic cardiomyopathy rats.

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