Abstract

The study is aimed at investigating the effects of Ginkgo biloba extract EGB761 on renal tubular damage and endoplasmic reticulum stress (ERS) in diabetic kidney disease (DKD). A total of 50 C57BL/6 N mice were randomly divided into the normal group, DKD group, DKD+EGB761 group (36 mg/kg), and DKD+4-phenylbutyrate (4-PBA) group (1 g/kg). The DKD model was replicated by high-fat diet combined with intraperitoneal injection of streptozotocin (STZ). Renal tubular epithelial cells (HK-2) were divided into the control group, high-glucose group (30 mmol/L), EGB761 group (40 mg/L, 20 mg/L, 10 mg/L), TM group, and TM+4-PBA group. After 8 weeks of administration, expressions of serum creatinine (Scr), blood urea nitrogen (BUN), 24 h urinary protein (24 h Pro), fasting blood glucose (FBG), β2-microglobulin (β2-MG), and retinol binding protein 4 (RBP4) of mice were tested. The pathological changes of renal tissue were observed. The expressions of extracellular matrix (ECM) accumulation and epithelial-mesenchymal transition (EMT) markers α-smooth muscle actin (α-SMA), E-cadherin, fibronectin, and collagen IV, as well as the ERS markers GRP78 and ATF6, were tested by Western blot, qPCR, immunohistochemistry, or immunofluorescence. EGB761 could decrease the Scr, BUN, 24 h Pro, and FBG levels in the DKD group, alleviate renal pathological injury, decrease urine β2-MG, RBP4 levels, and decrease the expression of α-SMA, collagen IV, fibronectin, and GRP78, as well as ATF6, while increase the expression of E-cadherin. These findings demonstrate that EGB761 can improve renal function, reduce tubular injury, and ameliorate ECM accumulation and EMT in DKD kidney tubules, and the mechanism may be related to the inhibition of ERS.

Highlights

  • Diabetic kidney disease (DKD) is one of the major microvascular complications of diabetic patients and has become the major causes of end-stage renal disease (ESRD) worldwide [1]

  • We investigated whether EGB761 can improve the DKD renal function

  • The results showed that serum creatinine (Scr), blood urea nitrogen (BUN), 24 h Pro, and fasting blood glucose (FBG) in the DKD group were significantly increased after 8 weeks of intragastric administration (P < 0:01)

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Summary

Introduction

Diabetic kidney disease (DKD) is one of the major microvascular complications of diabetic patients and has become the major causes of end-stage renal disease (ESRD) worldwide [1]. The etiology of DKD is complex [2, 3], including genetic factors, glycolipid metabolism disorder, inflammatory response, oxidative stress, autophagy, endoplasmic reticulum stress, and immune response It is pathologically manifested as extracellular matrix (ECM) deposition and glomerular basement membrane thickening and eventually develops into tubulointerstitial fibrosis and glomerulosclerosis. EGB761 is the standardized extract of Ginkgo biloba produced by the Schwabe company in Germany, and its main active component is flavonoids and terpenoids. It is widely used in clinical practice and well tolerated. We explored the effects of EGB761 on ECM accumulation and EMT in DKD mice and renal tubular epithelial cells (HK-2), as well as its mechanism. Our results provided evidence on the protective effect and mechanism of EGB761 against DKD

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