Astragaloside IV prevents kidney injury caused by iatrogenic hyperinsulinemia in a streptozotocin-induced diabetic rat model

Diabetic patients are able to manage their blood glucose with exogenous insulin but, ultimately, remain at risk of diabetic nephropathy (DN). Long-term use of insulin may lead to iatrogenic hyperinsulinemia, which has been suggested to cause kidney injury. However, there are no effective interventions for iatrogenic hyperinsulinemia leading to kidney damage. In the present paper, the hypothesis that astragaloside IV (AS-IV), a novel saponin purified from Astragalus membranaceus (Fisch) Bunge, may prevent DN in iatrogenic hyperinsulinemic diabetic rats through antioxidative and anti-inflammatory mechanisms was investigated. Diabetes was induced with streptozotocin (STZ) (55 mg/kg) by intraperitoneal injection in rats. At 1 week following STZ injection, the diabetic rats were treated with Levemir subcutaneously for 4 weeks. Diabetic rat insulin levels >30 mu U/ml were considered as iatrogenic hyperinsulinemia. Rats were divided into six groups (n=8 per group): Iatrogenic hyperinsulinemic rats, and iatrogenic hyperinsulinemic rats treated with Tempol and AS-IV at 2.5, 5 and 10 mg/kg/day, intragastric infusion, for 12 weeks. The normal rats were used as a non-diabetic control group. AS-IV ameliorated albuminuria, mesangial cell proliferation, basement membrane thickening and podocyte foot process effacement in iatrogenic hyperinsulinemic rats. In iatrogenic hyperinsulinemic rat renal tissues, malondialdehyde, interleukin-1 (IL-1 beta()), tumor necrosis factor-alpha (TNF-alpha), type IV collagen and laminin levels were increased, whereas glutathione peroxidase and superoxide dismutase activity levels were decreased. Nicotinamide adenine dinucleotide phosphate oxidase 4 expression and extracellular signal-regulated kinase 1/2 (ERK1/2) activation were upregulated, and canonical transient receptor potential cation channel 6 (TRPC6) protein expression was down-regulated. However, all these abnormalities were attenuated by AS-IV. These findings suggested that AS-IV prevented rat kidney injury caused by iatrogenic hyperinsulinemia by inhibiting oxidative stress, IL-1 beta and TNF-alpha overproduction, downregulating ERK1/2 activation, and upregulating TRPC6 expression.