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Introduction
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). Currently, there is no effective treatment for DN, and the prevention of the occurrence and progression of DN has become a serious medical challenge. Intensive insulin treatment has been shown in large prospective randomized studies to delay the onset and progression of DN in patients with type 1 and 2 diabetes (1) by lowering blood glucose levels and thus preventing hyperglycemia-associated damage (2). However, the use of insulin may result in iatrogenic hyperinsulinemia (3–6), which can also lead to kidney damage (4,5).
In the kidneys, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is the predominant source of reactive oxygen species (ROS). NADPH oxidase 4 (Nox4) is the key subunit of NADPH oxidase expressed in mesangial cells, and Nox4-derived ROS are the major contributor to renal morphological changes and functional abnormalities in DN (7). It has been reported that in vitro insulin treatment results in a rapid increase in H2O2 generation within podocytes, as well as an increase in the surface expression of Nox4 in cultured podocytes (8). High concentrations of insulin promoted pancreatic stellate cell proliferation and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, which resulted in pancreatic islet fibrosis (9). High concentrations of insulin may also contribute to renal extracellular matrix (ECM) accumulation in diabetes (10). These results suggested that high concentrations of insulin could promote oxidative stress, cell proliferation, and ECM accumulation in vitro. Oxidative stress serves an important role in DN. Regarding the role of ROS in the activation of transforming growth factor-β (TGF-β) signalling, it has been observed that NADPH oxidase exerts a key role in the TGF-β1-mediated activation of kidney myofibroblast and fibronectin extra domain A expression through the Smad3 and ERK signalling pathways (11). NADPH oxidase-mediated renal oxidative stress promotes albuminuria in DN (12). In addition, inhibition of Nox4 oxidase has been demonstrated to reduce whole kidney and glomerular hypertrophy in the diabetic cortex and glomeruli (13), suggesting that Nox4 may have a direct involvement in renal hypertrophy, perhaps via a mechanism involving Nox4-derived, ROS-mediated Akt/PKB and ERK1/2 activation (13). The detrimental role of NADPH oxidase in the development of DN has been further confirmed by a study in which treatment with NADPH oxidase...