Abstract
BackgroundDyslipidemia and lipotoxicity-induced insulin resistance, inflammation and oxidative stress are the key pathogeneses of renal damage in type 2 diabetes. Increasing evidence shows that whole-body low dose radiation (LDR) plays a critical role in attenuating insulin resistance, inflammation and oxidative stress.ObjectiveThe aims of the present study were to investigate whether LDR can prevent type 2 diabetes-induced renal damage and the underlying mechanisms.MethodsMice were fed with a high-fat diet (HFD, 40% of calories from fat) for 12 weeks to induce obesity followed by a single intraperitoneal injection of streptozotocin (STZ, 50 mg/kg) to develop a type 2 diabetic mouse model. The mice were exposed to LDR at different doses (25, 50 and 75 mGy) for 4 or 8 weeks along with HFD treatment. At each time-point, the kidney weight, renal function, blood glucose level and insulin resistance were examined. The pathological changes, renal lipid profiles, inflammation, oxidative stress and fibrosis were also measured.ResultsHFD/STZ-induced type 2 diabetic mice exhibited severe pathological changes in the kidney and renal dysfunction. Exposure of the mice to LDR for 4 weeks, especially at 50 and 75 mGy, significantly improved lipid profiles, insulin sensitivity and protein kinase B activation, meanwhile, attenuated inflammation and oxidative stress in the diabetic kidney. The LDR-induced anti-oxidative effect was associated with up-regulation of renal nuclear factor E2-related factor-2 (Nrf-2) expression and function. However, the above beneficial effects were weakened once LDR treatment was extended to 8 weeks.ConclusionThese results suggest that LDR exposure significantly prevented type 2 diabetes-induced kidney injury characterized by renal dysfunction and pathological changes. The protective mechanisms of LDR are complicated but may be mainly attributed to the attenuation of dyslipidemia and the subsequent lipotoxicity-induced insulin resistance, inflammation and oxidative stress.
Highlights
Diabetic nephropathy (DN) is one of the most severe complications of type 2 diabetes, which accounts for approximately 40% of all new cases who require renal replacement therapy [1,2]
These results suggest that low dose radiation (LDR) exposure significantly prevented type 2 diabetes-induced kidney injury characterized by renal dysfunction and pathological changes
Since nuclear factor E2-related factor-2 (Nrf-2) is a transcription factor that positively regulates the expression of several downstream genes playing an important role in the prevention of oxidative stress and damage, we examined several of its downstream genes to functionally evaluate Nrf-2 in the diabetic kidneys with and without LDR treatment
Summary
Diabetic nephropathy (DN) is one of the most severe complications of type 2 diabetes, which accounts for approximately 40% of all new cases who require renal replacement therapy [1,2]. The pathogeneses of kidney disease in type 2 diabetes are complicated, dyslipidemia and the subsequent lipotoxicity are regarded as critical inducers of renal damage under diabetic conditions [7,8,9]. Strong evidence showed that excessive FAs and their derivatives serve as signaling molecules that activate protein kinases [13] These kinases can impair insulin signaling, lead to insulin resistance [14,15]. It has been reported that lipotoxicity-induced insulin resistance plays a critical role in type 2 diabetes induced renal damage [16]. Dyslipidemia and lipotoxicity-induced insulin resistance, inflammation and oxidative stress are the key pathogeneses of renal damage in type 2 diabetes. Increasing evidence shows that whole-body low dose radiation (LDR) plays a critical role in attenuating insulin resistance, inflammation and oxidative stress
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