Elsevier

Tissue and Cell

Volume 76, June 2022, 101813
Tissue and Cell

Upregulation of BRD7 protects podocytes against high glucose-induced apoptosis by enhancing Nrf2 in a GSK-3β-dependent manner

https://doi.org/10.1016/j.tice.2022.101813Get rights and content

Highlights

  • BRD7 protected podocytes from HG-evoked injuries.

  • BRD7 enhanced Nrf2 activation via GSK-3β.

  • BRD7 defended against HG injuries of podocytes by Nrf2.

Abstract

Bromodomain-containing protein 7 (BRD7) is linked to a variety of pathophysiological conditions. However, it is still unclear whether BRD7 is connected with diabetic nephropathy. This research explored the relevance of BRD7 in diabetic nephropathy using high glucose (HG)-stimulated podocytes in vitro. BRD7 expression in podocytes was decreased after HG stimulation. Podocytes with forced BRD7 expression were protected from HG-induced apoptosis, oxidative stress and inflammation. Further data revealed that forced expression of BRD7 led to enhanced nuclear factor erythroid-2-related factor 2 (Nrf2) activation in HG-stimulated podocytes, associated with the upregulation of glycogen synthase kinase-3β (GSK-3β) phosphorylation. Reactivation of GSK-3β diminished BRD7-elicited Nrf2 activation. In addition, restraining of Nrf2 diminished the BRD7 overexpression-induced beneficial effects on HG-induced podocyte damage. Taken together, these data document that BRD7 defends against HG-induced podocyte damage by enhancing Nrf2 via regulation of GSK-3β. Our work indicates that the BRD7/GSK-3β/Nrf2 axis may play a key role in mediating podocyte injury in diabetic nephropathy.

Introduction

Diabetes is a common metabolic disorder characterized by hyperglycemia, which affects a large population worldwide (Cho et al., 2018). Constant exposure to hyperglycemia leads to numerous microvascular complications, including diabetic nephropathy (Kato and Natarajan, 2019). Diabetic nephropathy can progress to end-stage renal disease, which is a key contributor to mortality among diabetic patients (Sagoo and Gnudi, 2020). Podocyte injury is a primary cause of diabetic nephropathy in the early stage (Nishi and Nangaku, 2019). Podocytes are located at the outermost layer of the glomerular basement membrane, and they are highly vulnerable to hyperglycemia (Chen et al., 2019). Persistent hyperglycemia can induce excessive apoptosis, oxidative stress and inflammation, leading to podocyte injury (Anil Kumar et al., 2014). However, the underlying molecular mechanisms remain unclear. Identifying the key genes that contribute to hyperglycemia-induced podocyte damage may assist in the development of targeted strategies for treating diabetic nephropathy.

Bromodomain-containing protein 7 (BRD7), a member of the BRD proteins, has multiple functions and is involved in a broad range of pathophysiological conditions (Park and Lee, 2020). BRD7 was initially identified in nasopharyngeal carcinoma, but it has now been detected in a wide variety of tissues (Cuppen et al., 1999). BRD7 plays an essential role in embryonic development, and deficiency of this protein causes embryonic death (Kim et al., 2016). As a unique component of the switch/sucrose non-fermentable chromatin remodeling complex, BRD7 is expected to act as a transcriptional cofactor for many other proteins (Peng et al., 2006, Drost et al., 2010, Harte et al., 2010, Tae et al., 2011). BRD7 is differentially expressed in cancers and has a key function in carcinogenesis (Gao et al., 2016, Niu et al., 2020, Vivenza et al., 2020, Chen et al., 2021). Moreover, studies have described emerging roles of BRD7 in mediating cell senescence, differentiation, inflammation, obesity, hyperglycemia and glucose metabolism, which have been extensively studied (Heo et al., 2016, Wang et al., 2016, Zhao et al., 2017, Lee et al., 2019).

The cytoprotective protein nuclear factor erythroid-2-related factor 2 (Nrf2) orchestrates a cellular defense mechanism against adverse stressors (Nguyen et al., 2003). Nrf2 is a transcription factor that binds to antioxidant response elements (ARE), leading to enhanced expression of detoxifying enzymes (Chapple et al., 2012). The activation of Nrf2 can counteract the apoptosis, oxidative stress and inflammation induced by various adverse stressors, including high glucose (HG) concentrations (Uruno et al., 2015). Notably, enhanced Nrf2 activation is able to alleviate HG-evoked damages of podocytes (Wang et al., 2020, Feng et al., 2021, Xing et al., 2021, Yan et al., 2021). The activation of Nrf2 during HG exposure is regulated by glycogen synthase kinase-3β (GSK-3β) (Shen et al., 2019, Wang et al., 2019, Yu et al., 2020). GSK-3β is a crucial mediator of Nrf2, which accelerates the degradation and inactivation of Nrf2 (Salazar et al., 2006).

BRD7 plays a multifaceted role in a variety of pathophysiological conditions, yet its relevance in diabetic nephropathy remains unaddressed. Herein we explored the potential relevance of BRD7 in diabetic nephropathy using HG-stimulated podocytes in vitro. Considering that BRD7 is a critical regulator of GSK-3β (Golick et al., 2018) and GSK-3β mediates the activation of Nrf2 (Salazar et al., 2006), we seek to determine whether BRD7 regulates Nrf2 activation by GSK-3β in mediation of HG-induced podocyte injury.

Section snippets

Podocytes and high glucose treatments

An immortalized mouse podocyte line, MPC-5, was provided by BeNa Culture Collection (Xinxiang, China), and cultured according to the culture conditions specified by the manufacturer. MPC-5 cells were cultured in RPMI-1640 medium (Procell, Wuhan, China) containing 10% fetal bovine serum and 10 U/ml interferon-γ at 33 °C to induce cell proliferation. To induced cell differentiation, MPC-5 cells were maintained in RPMI-1640 medium without interferon-γ at 37 °C for 14 days. A cell model of diabetic

High glucose treatment decreases the BRD7 level in cultured podocytes

To test whether BRD7 is involved in mediating HG-induced podocyte damage, we first determined the effect of HG on the BRD7 level of cultured MPC-5 cells. The results showed that the BRD7 mRNA level in MPC-5 cells declined after HG treatment (Fig. 1A). Decreased BRD7 protein level in HG-exposed MPC-5 cells was confirmed by immunoblotting (Fig. 1B and C). Moreover, lower BRD7 protein level in HG-exposed MPC-5 cells was also observed by immunocytochemical staining (Fig. 1D). These data imply a

Discussion

In the current research, we identified BRD7 as a novel mediator of podocyte injury induced by HG. Our data demonstrate that overexpression of BRD7 confers protective effects in HG-challenged podocytes through the inhibition of apoptosis, oxidative stress and inflammation. Further investigation revealed that BRD7 is capable of enhancing Nrf2 activation through the regulation of GSK-3β, which underlies the BRD7-mediated protective effects against HG-induced podocyte injury (Fig. 8). Our work

CRediT authorship contribution statement

Xiangyou Yu: Conceptualization, Investigation, Writing – original draft. Ning Jiang: Investigation. Jing Li: I Conceptualization, Investigation, Writing – review & editing. Xiaofeng Li: Investigation. Shenglin He: Investigation.

Conflict of interest

The authors have no conflicts of interest to declare.

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