Puerarin Attenuates Diabetic Nephropathy by Promoting Autophagy in Podocytes.

Xueling Li,Yueyi Deng,Minggang Wei,Rong Zheng,Qingqing Zhu,Jiayi Yan,Yifei Zhong,Yichen Fan

doi:10.3389/fphys.2020.00073

Abstract

Puerarin, an active compound of radix puerariae, is a major compound used in Chinese herbal medicines to treat patients with diabetic nephropathy (DN). In the previous studies, we showed that puerarin exerts renoprotective effects in Streptozocin (STZ)-induced diabetic mice through activation of Sirt1 and anti-oxidative effects. Here, we further investigated the underlying mechanism mediating the renal protective effects of puerarin in DN. We studied the effects and mechanism of puerarin in STZ-induced diabetic mice and in cultured immortalized mouse podocytes treated with high glucose. We confirmed that puerarin ameliorated urinary albumin creatinine ratio and kidney injury in STZ-induced DN mice. We found that expression of heme oxygenase 1 (HMOX-1) and Sirt1 was suppressed in diabetic glomeruli but restored by puerarin treatment at both mRNA and protein levels. Additionally, we found that puerarin induced autophagy in the kidney of DN mice. In conditionally immortalized mouse podocytes, puerarin inhibited HG-induced apoptosis and restored the mRNA and protein levels of HMOX-1 and Sirt1. Interestingly, we showed that puerarin decreased liver kinase B1 (LKB1) acetylation, thereby promoting adenosine 5′-monophosphate-activated protein kinase-dependent autophagy. Knockdown of HMOX-1 and Sirt1 expression or treatment with the autophagy inhibitor 3-methyladenine abolished the protective effects of puerarin in HG-treated podocytes. Taken together, these results suggest that puerarin protects podocytes from diabetes-induced injury through HMOX1 and Sirt1-mediated upregulation of autophagy, a novel mechanism explaining its renal protective effects in DN.

Highlights

Diabetic nephropathy (DN) is a complication of diabetes and the leading cause of end stage renal disease worldwide (Yamahara et al, 2013)
The results showed that puerarin promoted autophagy and inhibited apoptosis through a mechanism involving the modulation of heme oxygenase 1 (HMOX-1), Sirt1, and the activation of AMPK
Mice with STZ-induced diabetes, which was confirmed by blood glucose levels > 250 mg/dl, and control mice were treated with puerarin (40 mg/kg) or DMSO

Summary

Introduction

Diabetic nephropathy (DN) is a complication of diabetes and the leading cause of end stage renal disease worldwide (Yamahara et al, 2013). Glomerular damage and proteinuria, which are associated with diabetes, lead to the development of tubulointerstitial lesions and endstage renal disease (Nath, 1992; Burton and Harris, 1996; Abbate et al, 2006). The development of which is associated with injury to podocytes (Nath, 1992). A reduction in podocytes density, which can be caused by apoptosis and detachment from the glomerular basement membrane, is a predictor of DN progression (Gunter et al, 2005; Weil et al, 2012).

Methods

Results

Conclusion