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Introduction
Chronic kidney disease is increasing worldwide at an annual rate of 8%, with the prevalence higher in developing countries (1). Diabetic nephropathy (DN) is a common underlying cause (2). DN is one of the most common microvascular complications of type 1 and type 2 diabetes mellitus (3), and is characterized by persistent proteinuria, progressive loss of renal function and morphological alterations, including glomerular hypertrophy, mesangial expansion, glomerular basement membrane thickening and interstitial fibrosis (4). Although metabolic and hemodynamic alterations, inflammation and activation of the renin-angiotensin system are involved in the pathogenesis of DN, the precise cause remains unclear. Emerging evidence suggests that oxidative stress serves a crucial role in the occurrence and development of DN (5).
The nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway is a crucial cytoprotective regulator in mammalian cells in response to endogenous and exogenous stress (6). Under physiological conditions, Nrf2 is inactivated by its inhibitory cytosolic protein, Kelch-like ECH-associated protein 1 (Keap1). When cells are exposed to redox modulators, Nrf2 is released from Keap1 and translocates into the nucleus (7). Nrf2, which binds to antioxidant response elements in the nucleus, regulates the transcription of antioxidant genes, including heme oxygenase 1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1). The induction of HO-1 and NQO1 has been considered to be adaptive cellular responses to oxidative stress (8).
Oxidative stress is defined as a disturbance in the balance between the production of reactive oxygen species (ROS) and antioxidant defenses (9). Diabetes may increase ROS production through a variety of pathways, including strengthening the autoxidation of glucose and increasing the formation of superoxides and advanced glycation end products (10). Excess amounts of ROS induce the activation of various transcription factors that increase the synthesis of extracellular matrix (ECM) and renal fibrosis, eventually leading to end-stage renal disease (11). A previous study demonstrated that renal fibrosis is one of the main pathological alterations in DN (12). Another report suggested that excess ROS may upregulate transforming growth factor-β (TGF-β) expression, which leads to over-production of ECM, thickening of the glomerular basement membrane and renal fibrosis (13). Therefore, the TGF-β family is considered an important pro-fibrotic mediator in fibrotic diseases (14).
Genistein (GEN) is a major isoflavone in soybeans that interacts with estrogen receptors in vivo