Abstract
Catalpol, an iridoid glycoside extracted from Rehmannia glutinosa, has been found to ameliorate diabetic nephropathy (DN), but the mechanism has not been clarified. Podocyte injury play a key role in the pathogenesis of DN. This study mainly investigated the protective effect and potential mechanism of catalpol on podocyte injury of DN in vivo and in vitro. The results indicated that the pathological features of DN in mice were markedly ameliorated after treatment with catalpol. Moreover, podocyte foot process effacement, and down-regulation of nephrin and synaptopodin expression in DN mice were also significantly improved after treatment with catalpol. In vitro, catalpol rescued disrupted cytoskeleton and increased migration ratio in podocytes induced by high glucose, the effect might be attributable to the inhibition of RhoA and Cdc42 activities but not Rac1. Furthermore, the impaired podocyte autophagy in DN mice was significantly enhanced after catalpol treatment. And catalpol also enhanced autophagy and lysosome biogenesis in cultured podocytes under high glucose condition. In addition, we found that catalpol could inhibit mTOR activity and promote TFEB nuclear translocation in vivo and in vitro experiments. Our study demonstrated that catalpol could ameliorate podocyte injury in DN, and the protective effect of catalpol might be attributed to the stabilization of podocyte cytoskeleton and the improvement of impaired podocyte autophagy.
Highlights
Diabetic nephropathy (DN) is a common diabetic microvascular complication, which has been one of the leading causes of end-stage renal disease and increases the risks of cardiovascular disease events and death (Georgianos and Agarwal, 2017; Cho et al, 2018; Ravindran et al, 2019)
Multiple clinical studies have confirmed that podocyte foot process effacement is found in DN patients, and such podocyte injury is accompanied with abnormal glomerular filtration function (Shankland, 2006; George et al, 2012; Hara et al, 2019)
Dynamic regulation of the podocyte foot process cytoskeleton plays a critical role in maintaining sustained glomerular filter function, and podocyte injury is accompanied by the cytoskeleton rearrangement, which is closely associated with foot process effacement and subsequent proteinuria (Tryggvason et al, 2006; Wiggins, 2007; Jefferson et al, 2011; Toffoli et al, 2018)
Summary
Diabetic nephropathy (DN) is a common diabetic microvascular complication, which has been one of the leading causes of end-stage renal disease and increases the risks of cardiovascular disease events and death (Georgianos and Agarwal, 2017; Cho et al, 2018; Ravindran et al, 2019). Multiple clinical studies have confirmed that podocyte foot process effacement is found in DN patients, and such podocyte injury is accompanied with abnormal glomerular filtration function (Shankland, 2006; George et al, 2012; Hara et al, 2019). Podocytes line the urinary side of the glomerular basement membrane, which are essential for maintenance of the structure and function of the glomerular filtration barrier through their interdigitating foot processes (Nagata, 2016). This unique function of podocytes depends on their complex cytoskeleton structure, the actin-rich foot processes. Given the key role of cytoskeleton dynamics, several previous studies have revealed that improving cytoskeleton dynamics would ameliorate DN (Kikuchi et al, 2007; Reiser and Sever, 2013; Lin and Susztak, 2016)
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