Ginkgo Biloba Extract EGB761 Ameliorates the Extracellular Matrix Accumulation and Mesenchymal Transformation of Renal Tubules in Diabetic Kidney Disease by Inhibiting Endoplasmic Reticulum Stress

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.

Metformin Ameliorates Epithelial–Mesenchymal Transition of Renal Tubular Epithelial Cells in Diabetes by Increasing Vitamin D Receptor Expression

“… 35 EMT is also one of the important causes of tubulointerstitial fibrosis in DKD, so EMT of renal tubular cells is considered to be a key process in the development of tubulointerstitial fibrosis in DKD. 36 By analyzing the expression of SMA, Ecad, and wound-healing assays, we found that EMT occurred in renal tubular epithelial cells in a high-glucose environment and recovered after metformin intervention. In addition, we found that the increase of VDR was accompanied by the down-regulation of EMT by calcitriol intervention.…”

Sirtuin Family and Diabetic Kidney Disease

“…Except for renal glucose metabolism, late renal changes of DKD mainly include renal tubular epithelial atrophy, collagen deposition, activation of myofibroblast and matrix, inflammatory cell influx, and epithelial-mesenchymal transition (EMT) ( 134 , 135 ). Studies showed that SIRT1 mainly regulated cell apoptosis induced by renal tubular oxidative stress ( 54 , 78 , 79 , 93 ), fibrosis ( 76 , 77 ) and EMT ( 77 , 93 ).…”

Fibrosis, the Bad Actor in Cardiorenal Syndromes: Mechanisms Involved

“…As ER stress inhibition has proved to ameliorate the fibrotic progression, it has been suggested that its blockade could be a new therapeutic approach for fibrosis [ 355 , 356 , 357 ]. One of the possible ways in which ER stress could lead to fibrosis is through fibroblast differentiation and collagen formation by TGF-β upregulation, as PERK and IRE1 activation have been seen to increase TGF-β expression [ 358 , 359 , 360 ].…”