Protective Effects of Berberine on Renal Injury in Streptozotocin (STZ)-Induced Diabetic Mice

Abstract

Diabetic nephropathy (DN) is a serious diabetic complication with renal hypertrophy and expansion of extracellular matrices in renal fibrosis. Epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells may be involved in the main mechanism. Berberine (BBR) has been shown to have antifibrotic effects in liver, kidney and lung. However, the mechanism of cytoprotective effects of BBR in DN is still unclear. In this study, we investigated the curative effects of BBR on tubulointerstitial fibrosis in streptozotocin (STZ)-induced diabetic mice and the high glucose (HG)-induced EMT in NRK 52E cells. We found that BBR treatment attenuated renal fibrosis by activating the nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling pathway in the diabetic kidneys. Further revealed that BBR abrogated HG-induced EMT and oxidative stress in relation not only with the activation of Nrf2 and two Nrf2-targeted antioxidative genes (NQO-1 and HO-1), but also with the suppressing the activation of TGF-β/Smad signaling pathway. Importantly, knockdown Nrf2 with siRNA not only abolished the BBR-induced expression of HO-1 and NQO-1 but also removed the inhibitory effect of BBR on HG-induced activation of TGF-β/Smad signaling as well as the anti-fibrosis effects. The data from present study suggest that BBR can ameliorate tubulointerstitial fibrosis in DN by activating Nrf2 pathway and inhibiting TGF-β/Smad/EMT signaling activity.

Effect of berberine on the renal tubular epithelial-to-mesenchymal transition by inhibition of the Notch/snail pathway in diabetic nephropathy model KKAy mice

“…Evidence is available that BBR protects human renal proximal tubular cells from hypoxia/reoxygenation injury by inhibiting endoplasmic reticulum and mitochondrial stress 31. Zhang et al26 have recently demonstrated that BBR can ameliorate tubulointerstitial fibrosis in DN by activating the Nrf2 pathway and inhibiting TGF-β/Smad/EMT signaling activity.…”

“…After growing tô80% confluence, the mRTECs were cultured in serum-free DMEM for 24 h at 37°C to arrest and synchronize cell growth. In vitro, the cells were divided into the following four groups: 1) NG, in which the cells were treated with DMEM containing 5.5 mM/L glucose; 2) HG group, in which the cells were treated with 30 mM/L glucose; 3) BBR group, in which the cells were treated with 30 mM/L glucose and 30 μM BBR;26 and 4) DAPT group, in which the cells were treated with 30 mM/L glucose after pretreatment with 10 μM/L N -[ N -(3,5-difluorophenacetyl)- l -alanyl]- S -phenylglycine t -butyl ester (DAPT; Sigma-Aldrich, Darmstadt, Germany) for 40 min. The mRTECs of the four groups were treated for 48 h and then used for the purposed experiments.…”

“…BBR treatment may restore the renal functional parameters, improve the glucose and lipid metabolism disorders, and suppress alterations of histologic and ultrastructural changes in the kidney 25. Moreover, BBR inhibits mesangial cell proliferation and extracellular matrix accumulation induced by high glucose (HG) and ameliorates tubulointerstitial fibrosis in DN, which suggests that BBR can be used as a potential drug for DN 26–30. Most importantly, a recent study has shown that BBR protects human renal proximal tubular cells from hypoxia/reoxygenation injury 31…”

Berberine for prevention of dementia associated with diabetes and its comorbidities: A systematic review

“…As shown in Table 6, berberine ameliorated renal inflammation and injury in diabetic models [79,83,85,86,90,96]. Underlying mechanisms include inhibition of kidney fibrosis via tumor growth factor (TGF)- signaling suppression and Nrf2 activity enhancement [76,77,80,82,86,91,93,144], suppression of HG-induced mesangial cell proliferation and hypertrophy via suppression of NF-B and AP-1 [81,84,90], and attenuation of ECM accumulation [87], possibly by restoring β-arrestin [88] and E prostanoid receptor 4 (EP4)-Gαs-cAMP signaling pathway [83,85]. In addition, berberine directly protected podocytes from HG-induced injury in vitro [23,94], possibly by inhibiting podocyte apoptosis via AMPK-dependent autophagy induction [92].…”

Action Mechanisms and Therapeutic Targets of Renal Fibrosis

“…In the context of renal fibrosis, [57]. Similarly, renal fibrosis in a variety of animal models were mitigated via TGF-β/Smad pathways by administration of natural products, such as GQ5 [58], curcumin [59,60], arctigenin [61], resveratrol [62], sinomenine [63], berberine [64,65], leonurine [66], rutin [67], bergenin [68], oxymatrine [69,70], oleanolic acid [71], tanshinone IIA [72], astragaloside IV [73,74], (+/-)sinensilactam A [75] and epigallocatechin-3-gallate [76]. Besides, inflammation could in the activation of immune cells, including macrophages, dendritic cells and T cells.…”