Upregulation of BRD7 protects podocytes against high glucose-induced apoptosis by enhancing Nrf2 in a GSK-3β-dependent manner
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.
References (42)
- et al.
Nrf-2 mediated heme oxygenase-1 activation contributes to the anti-inflammatory and renal protective effects of Ginkgo biloba extract in diabetic nephropathy
J. Ethnopharmacol.
(2021) - et al.
Crosstalk between Nrf2 and the proteasome: therapeutic potential of Nrf2 inducers in vascular disease and aging
Int. J. Biochem. Cell Biol.
(2012) - et al.
IDF Diabetes Atlas: global estimates of diabetes prevalence for 2017 and projections for 2045
Diabetes Res. Clin. Pract.
(2018) - et al.
Identification and molecular characterization of BP75, a novel bromodomain-containing protein
FEBS Lett.
(1999) - et al.
Perilipin 5 ameliorates high-glucose-induced podocyte injury via Akt/GSK-3beta/Nrf2-mediated suppression of apoptosis, oxidative stress, and inflammation
Biochem. Biophys. Res. Commun.
(2021) - et al.
PTPN14 deficiency alleviates podocyte injury through suppressing inflammation and fibrosis by targeting TRIP6 in diabetic nephropathy
Biochem. Biophys. Res. Commun.
(2021) - et al.
Podocyte lipotoxicity in diabetic kidney disease
Kidney Int.
(2019) - et al.
BRD7 regulates XBP1s’ activity and glucose homeostasis through its interaction with the regulatory subunits of PI3K
Cell Metab.
(2014) - et al.
Glycogen synthase kinase-3beta inhibits the xenobiotic and antioxidant cell response by direct phosphorylation and nuclear exclusion of the transcription factor Nrf2
J. Biol. Chem.
(2006) - et al.
Sulfiredoxin-1 alleviates high glucose-induced podocyte injury though promoting Nrf2/ARE signaling via inactivation of GSK-3beta
Biochem. Biophys. Res. Commun.
(2019)
The Keap1-Nrf2 system and diabetes mellitus
Arch. Biochem. Biophys.
FGF1(DeltaHBS) ameliorates chronic kidney disease via PI3K/AKT mediated suppression of oxidative stress and inflammation
Cell Death Dis.
Effects of ROS-relative NF-kappaB signaling on high glucose-induced TLR4 and MCP-1 expression in podocyte injury
Mol. Immunol.
Klotho ameliorates diabetic nephropathy by activating Nrf2 signaling pathway in podocytes
Biochem. Biophys. Res. Commun.
Bromodomain-containing protein 7 deficiency augments atherosclerotic lesions in ApoE(-/-) mice
Biochem. Biophys. Res. Commun.
BRD4 contributes to high-glucose-induced podocyte injury by modulating Keap1/Nrf2/ARE signaling
Biochimie
Molecular and cellular events mediating glomerular podocyte dysfunction and depletion in diabetes mellitus
Front. Endocrinol.
BRD7 inhibits tumor progression by positively regulating the p53 pathway in hepatocellular carcinoma
J. Cancer
The protective effect and mechanism of catalpol on high glucose-induced podocyte injury
BMC Complement. Alter. Med.
BRD7 is a candidate tumour suppressor gene required for p53 function
Nat. Cell Biol.
BRD7 acts as a tumor suppressor gene in lung adenocarcinoma
PLoS One
Cited by (2)
Nrf2 signaling in diabetic nephropathy, cardiomyopathy and neuropathy: Therapeutic targeting, challenges and future prospective
2023, Biochimica et Biophysica Acta - Molecular Basis of DiseaseBRD7 restrains TNF-α-induced proliferation and migration of airway smooth muscle cells by inhibiting notch signaling
2022, Experimental Lung Research