Icariin Prevents Extracellular Matrix Accumulation and Ameliorates Experimental Diabetic Kidney Disease by Inhibiting Oxidative Stress via GPER Mediated p62-Dependent Keap1 Degradation and Nrf2 Activation.

Kai Wang,Zhenzhen Pan,Xin Gao,Xiniao Wang,Wenhui Yao,Xiulan Zheng,Xuansheng Ding

doi:10.3389/fcell.2020.00559

Abstract

The present study aimed to determine whether icariin could attenuate type 1 diabetic nephropathy (T1DN) induced by streptozotocin (STZ) after 4 weeks or not. Therefore, its therapeutic effect on diabetic kidney disease was investigated in view of reactive oxygen (ROS) and extracellular matrix (ECM) generation in human glomerular mesangial cells under high glucose. To establish the participation and the key role of GPER and Nrf2 in ECM deposition, a combination of G15 (antagonist of GPER) or siGPER and siNrf2 were performed, respectively. The results showed that T1DN can be significantly inhibited by oral icariin, evidenced by improvement of 24 h urinary volume, 24 h proteinuria, microalbuminuria, and histopathological changes of kidney. Icariin decreased the levels of intracellular superoxide anion, impeded the generation of fibronectin and increased the expression and activity of antioxidant enzymes in the human glomerular mesangial cells treated with high glucose. It acted as a GPER activator, increased dissociation of Nrf2/Keap1 complexes, combination of Keap1/p62 complexes, Nrf2 translocation to nuclear, Nrf2/ARE DNA binding activity, and ARE luciferase reporter gene activity in glomerular mesangial cells. The Nrf2 inhibitor ML385 or siNrf2 obviously abolished extracellular matrix (ECM) generation inhibited by icariin. Furthermore, icariin-induced Nrf2 activation was mainly dependent on p62-mediated Keap1 degradation, which functions as an adaptor protein during autophagy. The GPER antagonist G15 and siGPER obviously abolished the above effects by icariin. Taken together, the present study demonstrated that the therapeutic effects of icariin on type 1 diabetic nephropathy in rats via GPER mediated p62-dependent Keap1 degradation and Nrf2 activation.

Highlights

Diabetic nephropathy (DN), a common devastating complication of both types of diabetes and supervenes as the result of microvascular lesions in the renal glomeruli, is often associated with increased cardiovascular mortality and reduced life quality
Our results showed that diabetic rats took more water and food, along with the hyperglycemia and high blood pressure, indicating that a DN animal model was successfully established
Icariin dose-dependently attenuated the progression of DN, as exhibited by decreased weight loss (Figure 3A) and inhibited the increase in water (Figure 3C), food intake (Figure 3B) and blood pressure (Figure 3G), but no significant changes in blood glucose (Figure 3D), fasting insulin level (Figure 3E) and insulin sensitivity index (Figure 3F) were observed in the different groups, which suggested that the improvement of diabetes symptoms by oral icariin was probably independent of glycemic control

Summary

Introduction

Diabetic nephropathy (DN), a common devastating complication of both types of diabetes and supervenes as the result of microvascular lesions in the renal glomeruli, is often associated with increased cardiovascular mortality and reduced life quality. The end-stage renal disease incidence can be 4–17% within 25 years after the diagnoses of T1D. Over 20% of patients with T2D already have diabetic nephropathy at the same time of diabetes (Parving et al, 1988), of whom a further 35% develop DN mostly in 10 years. Known as glomerulosclerosis, is associated with progressive, uninterrupted scarring of the glomerulus (Wolf and Ziyadeh, 1999; Zheng et al, 2004). Diabetic induce oxidative stress and excessive deposition of extracellular matrix (ECM) in the mesangium of the glomerulus (Mason and Wahab, 2003). The phenomenon is attributed to the loss of glomerular mesangial cell viability, which is a crucialpathological change in the diabetes-mediated renal injury (Ortiz-Munoz et al, 2010; Loeffler et al, 2011)

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Conclusion