Abstract
Glucose-induced reactive oxygen species (ROS) production initiates podocyte apoptosis, which represents a novel early mechanism leading to diabetic nephropathy (DN). Here, we tested the hypothesis that Astragaloside IV(AS-IV) exerts antioxidant and antiapoptotic effects on podocytes under diabetic conditions. Apoptosis, albuminuria, ROS generation, caspase-3 activity and cleavage, as well as Bax and Bcl-2 mRNA and protein expression were measured in vitro and in vivo. Cultured podocytes were exposed to high glucose (HG) with 50, 100 and 200 µg/ml of AS-IV for 24 h. AS-IV significantly attenuated HG-induced podocyte apoptosis and ROS production. This antiapoptotic effect was associated with restoration of Bax and Bcl-2 expression, as well as inhibition of caspase-3 activation and overexpression. In streptozotocin (STZ)-induced diabetic rats, severe hyperglycemia and albuminuria were developed. Increased apoptosis, Bax expression, caspase-3 activity and cleavage while decreased Bcl-2 expression were detected in diabetic rats. However, pretreatment with AS-IV (2.5, 5, 10 mg·kg−1·d−1) for 14 weeks ameliorated podocyte apoptosis, caspase-3 activation, renal histopathology, podocyte foot process effacement, albuminuria and oxidative stress. Expression of Bax and Bcl-2 mRNA and protein in kidney cortex was partially restored by AS-IV pretreatment. These findings suggested AS-IV, a novel antioxidant, to prevent Glucose-Induced podocyte apoptosis partly through restoring the balance of Bax and Bcl-2 expression and inhibiting caspase-3 activation.
Highlights
Diabetic nephropathy (DN) is an important and common complication of both type 1 and type 2 diabetes leading to endstage renal disease (ESRD)
The cells were divided into the following groups: (1) normal glucose group (NG) as controls incubated in RPMI 1640 containing 5 mM glucose, (2) high glucose group (HG) incubated in RPMI 1640 containing 30 mM glucose, (3) mannitol group (MA) incubated in NG medium supplemented with 25 mM D-mannitol (Sigma, USA) as an osmotic control, (4) AS-IV group incubated in HG medium treated with different concentrations of AS-IV(50, 100, 200 mg/ ml) for 24 h
AS-IV protected against HG-induced podocyte apoptosis in a concentration-dependent manner, with the maximal effect achieved at a dose of 200 mg/ml (Fig. 1A)
Summary
Diabetic nephropathy (DN) is an important and common complication of both type 1 and type 2 diabetes leading to endstage renal disease (ESRD). There is common agreement that podocytes have a central role in the development of proteinuria, which is a hallmark of almost all glomerular diseases [1]. In human type 1 and type 2 diabetes mellitus [2,3,4], the podocyte number is reduced in individuals with DN, and in subjects with short duration of diabetes before the onset of microalbuminuria [4,5]. The study demonstrated that podocyte apoptosis coincided with the onset of urinary albumin excretion and preceded apparent podocyte loss in experimental diabetic models [7]. These studies indicate that DN may directly stem from podocyte injury. Podocytes become a promising target for the development of new renal-protective drugs for DN
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