Abstract
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.
Highlights
Diabetes mellitus (DM) is the most common metabolic disorder that negatively affects all aspects of body metabolism, contributing to multiple complications and dysfunction of the tissues (Carlsson, Andersson & Ahlbom, 2016; Sharma, Nazareth & Petersen, 2016)
After 6 weeks of treatments with valsartan and LCZ696 in the diabetic rats, significant reduction (P < 0.001; DV vs. detected in GSH (DC) and DSV vs. DC) in serum glucose levels were seen with the mean serum glucose values were 114.6 ± 8.6 mg/dl in DV group and 131.2 ± 11 mg/dl in DSV
Urea level observed in the DC group was 32.2 ± 2.6 mg/dl and after 6 weeks of treatments levels noticed in DV were 24.2 ± 0.9 mg/dl (P < 0.001 compared to DC) and in DSV 22.3 ± 0.9 mg/dl (P < 0.001 compared to DC)
Summary
Diabetes mellitus (DM) is the most common metabolic disorder that negatively affects all aspects of body metabolism, contributing to multiple complications and dysfunction of the tissues (Carlsson, Andersson & Ahlbom, 2016; Sharma, Nazareth & Petersen, 2016). Nephropathy is a common cause of mortality in patients with DM (Skupien et al, 2019) This syndrome is characterized by the progressive loss of renal functions and persistent albuminuria (Lim, 2014) followed by certain pathological changes such as glomerular mesangial expansion and accumulation of extracellular matrix as indicators of the incidence of glomerulosclerosis (Peng et al, 2019). Time course therapy with LCZ696 and valsartan in diabetic rats resulted in significant reduction of serum glucose, urea and creatinine 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). Present data suggest that LCZ696 has sufficient therapeutic potential to restrict DN progression through inhibiting inflammation, oxidative stress and glomerulosclerosis
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