Abstract
BackgroundDiabetic nephropathy (DN) is a serious complication of diabetes mellitus (DM) with limited treatment options. DN leads to progressive renal failure and accelerates rapidly into end-stage renal disease. Astragalus mongholicus Bunge and Panax notoginseng (Burkill) F.H. Chen formula (APF) is a traditional Chinese medicine (TCM) formula widely used to treat chronic kidney diseases (CKD) in the clinic in the southwest of China. The aim of this study is to explore how APF and its related TCM theory work on DN and whether mTOR/PINK1/Parkin signaling plays a part in this process.MethodsHPLC was used for preliminary chemical analysis and quantitative analysis of the five components of APF. An in vivo autophagy deficiency model was established in C57BL/6 mice by streptozocin (STZ) combined with a high-fat and high-sugar diet, while the in vitro autophagy deficiency model was induced with high glucose (HG) in renal mesangial cells (RMCs). Renal histopathology staining was performed to investigate the extents of inflammation and injury. Real time-PCR and Western blotting techniques were utilized to assess autophagy-related proteins.ResultsAPF significantly ameliorated renal injury in DN mice, specifically restoring blood urea nitrogen, serum creatinine, and 24-hour albuminuria. APF also reduced the mRNA and protein expressions of TNFα, IL-1β, and IL-6 in STZ-induced DN mice. Furthermore, APF improved the autophagy deficiency induced by STZ in vivo or HG in vitro, as revealed by changes in the expressions of mTOR, PINK1, Parkin, Beclin 1, p62, and LC3B. Notably, inhibition of autophagy with 3-methyladenine in APF-treated RMCs aggravated cellular damage and altered mTOR/PINK1/Parkin signaling, indicating that APF rescued HG damage through promoting autophagy.ConclusionAPF may protect the kidneys from inflammation injuries in DN by upregulating autophagy via suppressing mTOR and activating PINK1/Parkin signaling. This experimental evidence strongly supports APF as a potential option for the prevention and treatment of DN.
Highlights
Diabetic nephropathy (DN) is a severe microangiopathic complication that occurs in about 35%~ 45% of type 2 diabetes mellitus (DM) patients and is attributed to 44% of the end-stage renal disease (ESRD) (Zheng et al, 2018)
In order to better understand the effectiveness of this formula from the perspective of effective ingredients, high-performance liquid chromatography (HPLC) technology was applied to detect the content of main component monomers that can be extracted from the APF as a whole
serum creatinine (Scr) and serum blood urea nitrogen (BUN) can clearly reflect the status of the kidney, as is recognized in both clinical and scientific research, and 24-h albuminuria can reflect the degree of glomerular dysfunction
Summary
Diabetic nephropathy (DN) is a severe microangiopathic complication that occurs in about 35%~ 45% of type 2 diabetes mellitus (DM) patients and is attributed to 44% of the end-stage renal disease (ESRD) (Zheng et al, 2018). HO-1 functions as a beneficial enzyme mediating anti-inflammation and anti-oxidation through multiple pathways deriving mainly from macrophages (Nakamura et al, 2017; Zhan et al, 2018) Based on this phenomenon, we preliminarily hypothesized that autophagy could reduce the intracellular inflammation level by degrading intracellular wastes. We believe there is sufficient evidence to prove that restoring autophagy helps to alleviate inflammation in kidneys, followed by improving the general condition of the kidney, which can play an important role in the occurrence and development of DN. This means that it may be an effective target for DN treatment. The aim of this study is to explore how APF and its related TCM theory work on DN and whether mTOR/PINK1/Parkin signaling plays a part in this process
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