Abstract
Diabetic nephropathy (DN) is a common diabetes associated complication. Thus, it is important to understand the pathological mechanism of DN and find the appropriate therapeutic strategy for it. Dl-3-n-Butylphthalide (DL-NBP) has anti-inflammatory and antioxidant effects, and been widely used for the treatment of stroke and cardiovascular diseases. In this study, we selected three different doses (20, 60, and 120 mg⋅kg−1 d−1) of DL-NBP and attempted to elucidate its role and molecular mechanism underlying DN. We found that DL-NBP, especially at the dose of 60 or 120 mg⋅kg−1 d−1, could significantly ameliorate diabetes-induced elevated blood urea nitrogen (BUN) and creatinine level, and alleviate renal fibrosis. Additionally, the elevated expressions of collagen and α-smooth muscle actin (α-SMA) in the kidney from db/db mice were found to be significantly suppressed after DL-NBP treatment. Furthermore, mechanistic studies revealed that DL-NBP inhibits pro-inflammatory cytokine levels, thereby ameliorating the development of renal fibrosis. Moreover, we found that DL-NBP could not only reduce the endoplasmic reticulum stress (ERS), but also suppress activation of the renin-angiotensin system to inhibit vascular endothelial growth factor (VEGF) level, which subsequently reduces the podocyte apoptosis in kidney of db/db mice. In a word, our findings suggest that DL-NBP may be a potential therapeutic drug in the treatment of DN.
Highlights
Diabetic nephropathy (DN) is a microvascular complication of diabetes that can lead to end-stage renal disease (ESRD)
It was worth noting that the average level of blood urea nitrogen (BUN) and Cr in serum from db/db mice were significantly higher than those in db/m mice (Figures 2A,B), which suggested that chronic hyperglycemia is likely to cause the dysfunction of kidney
We found that diabetes significantly increases the expressions of angiotensin II receptor type 1 (AT1) and angiotensin II generating enzyme (ACE) in the kidney (Figures 7A–C), which are restored by DL-NBP treatment (Figures 7A–C)
Summary
Diabetic nephropathy (DN) is a microvascular complication of diabetes that can lead to end-stage renal disease (ESRD). Hyperglycemia, inflammation, endoplasmic reticulum stress (ERS), and disorder of renin-angiotensin system (RAS) are the important causative factors for the occurrence and development of DN (Ruggenenti et al, 2010; Kanwar et al, 2011; Navarro-González et al, 2011). As it is known, RAS plays a key role in the development of DN, which can increase glomerular capillary pressure and permeability, stimulate the proliferation and hypertrophy of renal cells, and affect the function of glomerular filtration barrier (GFB) (Guo et al, 2017). During diabetic condition, elevated Ang II has been reported to induce the vascular endothelial growth factor (VEGF) overexpression, podocyte damage, and GFB destruction (Mironidou-Tzouveleki et al, 2011; Zheng et al, 2019)
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