Clusterin suppresses spermatogenic cell apoptosis to alleviate diabetes‐induced testicular damage by inhibiting autophagy via the PI3K/AKT/mTOR axis

Abstract

Background informationDiabetes‐induced testicular dysfunction is characterised by abnormal apoptosis of spermatogenic cells, but the underlying mechanism is poorly understood. This study aimed to investigate the roles of clusterin (CLU) in testicular damage associated with diabetes pathogenesis, as well as the molecular mechanism.A rat diabetes model was established using streptozocin, and the mouse spermatogenic cell line GC‐1 spg was treated with high glucose as a cellular model. CLU was overexpressed in GC‐1 spg cells, followed by detection of serum testosterone, cell proliferation, cell apoptosis and autophagy.ResultsCLU expression was significantly reduced and LC3 expression was elevated in testis tissues in the rat diabetes model and high glucose‐treated GC‐1 spg cells. High glucose led to suppressed viability, enhanced apoptosis, reduced Bcl‐2 expression, elevated Bax expression and cleavage of Caspase‐3/‐9 in GC‐1 spg cells, and these effects were abrogated by CLU overexpression. Additionally, CLU overexpression repressed LC3 and Beclin‐1 expression, reduced the LC3II/LC3I ratio and promoted p62 expression in GC‐1 spg cells in the presence of high glucose, and these effects were all mitigated by rapamycin treatment. Inhibition of PI3K/AKT/mTOR signalling with LY294002 activated autophagy in CLU‐overexpressing GC‐1 spg cells under high glucose conditions. CLU overexpression repressed autophagy and alleviated testicular damage in diabetic rats, which was also abrogated by LY294002 treatment.ConclusionsCLU expression is suppressed during diabetes‐induced testicular damage, whereas CLU overexpression alleviates diabetes‐induced testicular damage by activating PI3K/AKT/mTOR signalling to inhibit autophagy and further repress spermatogenic cell apoptosis.

SerpinA3N attenuates ischemic stroke injury by reducing apoptosis and neuroinflammation

“…Previous reports demonstrated that clusterin enhances neuronal survival via activating the PI3K/Akt and other related signaling pathways. [37][38][39]64 Accordingly, we found that serpinA3N enhanced the activation of the Akt pathway in vivo and in vitro, which is associated with a neuroprotective effect. [65][66][67][68] A drawback of the present study is that we did not perform ser-pinA3N knockout or knockdown, given that serpinA3N itself is upregulated post-MCAO.…”

“…Previous reports demonstrated that clusterin enhances cell survival via activating the PI3K/Akt pathways in retinal glial cells and in other peripheral tissues such as the pulmonary artery, the liver, and the sperm cells. [37][38][39][40] To explore whether this serves as a potential mechanism for serpinA3N-afforded neuronal cell survival, we detected the Akt activation and its downstream protein, mechanistic target of rapamycin (mTOR), both in vitro and in vivo. In neuronal cultures subjected to OGD/R, serpinA3N treatment increased both Akt activation and mTOR activation, indicated by the ratios of phospho-Akt (Figure 6A-B).…”

miR-27b-3p Improved High Glucose-Induced Spermatogenic Cell Damage via Regulating Gfpt1/HBP Signaling

“…Recently, abnormal apoptosis of spermatogenic cells has been identified as a key cellular event related to DM-related testicular dysfunction [20]. In addition, a previous study showed that autophagy was an effective mechanism which was capable of promoting spermatogenic cell apoptosis in response to adverse conditions (such as HG) [6]. Inhibition of apoptosis and autophagy of spermatogenic cells is considered to be a promising strategy for the treatment of DM-induced abnormal testicular function [21, 22].…”

“…Male DM patients will have a series of symptoms such as testicular endocrine dysfunction, testicular sperm level, and decreased exercise capacity [5]. The main pathological manifestation of testicular dysfunction caused by DM is decreased spermatogenesis, which may be attributed to decreasing proliferation of spermatogenic cells and increased apoptosis [6]. Therefore, exploring the regulation mechanism of the abnormal proliferation and apoptosis of spermatogenic cells in DM is of great significance for novel therapeutics.…”

N6-Methyladenosine Methyltransferase METTL3 Alleviates Diabetes-Induced Testicular Damage through Modulating TUG1/Clusterin Axis

“…Clusterin was elevated in diabetic nephropathy and inhibited apoptosis of podocytes [ 16 ]. Importantly, clusterin was downregulated in testis tissues of diabetic rats, and upregulation of clusterin could rescue cell viability and inhibited cell apoptosis in HG-treated GC-1 spg cells via regulating phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling [ 17 ]. Accordingly, elucidating the upstream regulatory mechanism of clusterin maybe help us better understand the mechanism of DTID.…”