Astragaloside IV attenuates proteinuria in streptozotocin-induced diabetic nephropathy via the inhibition of endoplasmic reticulum stress

Abstract

BackgroundDiabetic nephropathy (DN) is a major cause of Chronic Kidney Disease and End-Stage Renal Disease throughout the world; however, the reversibility of diabetic nephropathy remains controversial. Endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of DN. Astragaloside IV (AS-IV) is derived from Astragalus membranaceus (Fisch) Bge, a widely used traditional herbal medicine in China, and has diverse pharmacological activities including the attenuation of podocyte injury and amelioration of proteinuria in idiopathic nephrotic syndrome. The present study aimed to investigate the effect and mechanism of AS-IV on proteinuria in the rat streptozotocin (STZ)-induced model of diabetes.MethodsMale Sprague–Dawley (SD) rats were randomly divided into four groups: normal control (Normal group), diabetic nephropathy (Model group), diabetic nephropathy plus AS-IV treatment (AS-IV group) and diabetic nephropathy plus 4-phenyl butyric acid treatment (PBA group). ER stress was induced in cultured human podocytes, pretreated with or without AS-IV, with tunicamycin (TM). At the end of 8 weeks, serum creatinine (Scr), blood urea nitrogen (BUN) and 24-hour urinary protein excretion rate (UAER) were determined. Renal morphology was examined after periodic acid-Schiff staining of kidney sections. Apoptosis of podocytes was measured by flow cytometry. The total expression and phosphorylation of eIF2α, PERK and JNK, and the expression of CHOP and cleaved caspase-3 were determined by western blotting. The expression of glucose-regulated protein 78 (GRP78) and 150 kDa oxygen-regulated protein (ORP150) mRNA and protein was determined by real-time PCR and western blotting respectively.ResultsAS-IV treatment significantly reduced urinary albumin excretion, plasma creatinine and blood urea nitrogen levels, and prevented the mesangial matrix expansion and increase in mean mesangial induced by STZ. AS-IV also prevented the phosphorylation of eIF2α, PERK and JNK, and inhibited the expression of GRP78 and ORP150 markedly, both in vivo and in vitro. AS-IV inhibited the TM-induced apoptosis of podocytes, concomitant with decreased CHOP expression and cleaved caspase-3.ConclusionsThis study supports the hypothesis that AS-IV reduces proteinuria and attenuates diabetes, which is associated with decreased ER stress. This might be an important mechanism in the renoprotective function of AS-IV in the pathogenesis of DN.

Transthyretin Exerts Pro-Apoptotic Effects in Human Retinal Microvascular Endothelial Cells Through a GRP78-Dependent Pathway in Diabetic Retinopathy

“…GRP78 (BiP) is a 78-kDa protein chaperone [26,27] that has been proven to prevent the cell death caused by disturbance of endoplasmic reticulum (ER) homeostasis [28] and to mediate essential components of ER stress-induced apoptosis [31][32][33]. Fluorescent labeling and immunofluorescence staining indicated that TTR efficiently crossed cell membrane and nuclear membrane; the localization of TTR and GRP78 partially overlapped in and around the nuclei.…”

Synergistic Inhibitory Effect of Traditional Chinese Medicine Astragaloside IV and Curcumin on Tumor Growth and Angiogenesis in an Orthotopic Nude-Mouse Model of Human Hepatocellular Carcinoma

“…mongholicus (Bge.) Hsiao and has various pharmacological activities, including anti-tumor, anti-inflammatory and anti-diabetic (3,4). Curcumin (diferuloylmethane) is the chief component of the spice turmeric and is derived from the rhizome of the East Indian plant Curcuma longa.…”

Endoplasmic reticulum stress and renal lesion in mice with combination of high-fat diet and streptozotocin-induced diabetes

“…Though we successfully established a mice model with nephropathy and observed the upregulated GRP78 and CHOP in this model, we were not able to directly prove that ER stress did participate in the renal lesion of diabetes. Some study has proved that ER stress contributed to the renal injury in diabetic rats induced by STZ 10,21,22 , thus we conjecture that both models share the same mechanism on the onset of DN. We believe that this mechanism on DN can be explored by inhibiting the ER stress using an ER stress inhibitors such as 4-phenylbutyric acid (4-PBA).…”

“…Accumulating evidence has revealed that ER stress contributed to insulin resistance, aggravated β-cell burden, and reduced β-cell mass, resulting in T2DM 9 . Though two recent studies have proved that ER stress is activated in the kidney of diabetic rats 10,11 , whether ER stress influences renal tissue in Kunming (KM) mice treated with high-fat diet and streptozotocin (STZ) is poorly understood. In this study, we aim to test whether renal lesion occurs in the diabetic Kunming mice induced by combination of high-fat diet and STZ.…”