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Introduction
Diabetic nephropathy (DN) is by far the most common cause of end-stage renal disease (ESRD) in industrial countries, making up approximately 45% of all new ESRD cases in the United States (1). Its pathogenesis is a chronic and complex process. At the later stages of DN, the gradual decline of renal function, tubular atrophy and interstitial fibrosis occurs (2). Several studies have shown that apoptosis could be considered a vital component in the processes of DN (3–6). However, several pathways can induce apoptosis, including the intrinsic pathway, the extrinsic pathway and the endoplasmic reticulum stress (ERS) pathway (7).
The ER is the site of lipid biosynthesis, protein folding and protein maturation in eukaryotic cells. The ER is extremely sensitive to the factors that affect intracellular energy levels, the oxidation state, and the calcium concentration. When the cells receive a shock (such as from hypoxia, and toxic drugs), the ER environment is destroyed, inducing calcium metabolism disorder, ER function disorder, an increase in unfolded or misfolded proteins in the ER, and calcium imbalance. We designated this state as ERS. One major response of ERS is dissociation of glucose-regulated protein 78 (GRP78) with transmembrane receptor which leads to its activation to deal with the accumulated unfolded proteins (8). Phosphorylated-extracellular signal-regulated kinase (p-ERK) is transmembrane protein in the ER, which plays a signal transduction role. p-ERK is known as an initial, crucial protector for survival during even mild stress (9). Slight and medium ERS can protect the cell from death, but severe ERS induces Caspase-12-dependent cell apoptosis (9). Since the ERS has both protective and deleterious features, a better understanding of the molecular pathways of the ERS could reveal novel therapeutic strategies in chronic renal diseases, including diabetic kidney disease.
Grape seed proanthocyanidin extracts (GSPE) are derived from grape seeds and have been shown to possess potent antioxidant, anti-inflammatory, radical-resistance, anti-tumor, and cardiovascular protecting properties (10–12). In this study, we treated a streptozotocin (STZ)-induced DN rat model with GSPE to investigate the effect of GSPE on STZ-induced DN. In order to ascertain whether a protective effect of GSPE on DN occurred through the inhibition of ERS-induced apoptosis, We investigated the protein expression levels of GRP78, p-ERK and Caspase-12 by Western blotting and immunohistochemical staining. We used TUNEL...