Effects of prokineticin 2 on testicular inflammation in rats

Li, Ying; Wang, Jiaojiao; Yu, Lili; Zhao, Kai; Chen, Biao; Li, Cuiling; Yang, Fan; Yuan, Hongfang; Zhang, Huiping

doi:10.1111/aji.12843

Cited by 9 publications

(17 citation statements)

References 32 publications

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“…Moreover, after being injected with the PK2 protein through the rete testis of adult rats to establish the PK2 overexpression model, the testes presented inflammatory histological changes with an increased infiltration of interstitial cells and disintegration of the seminiferous epithelium. 12 Previous research has suggested that varicocele is an inflammation-activated state that is associated with increased levels of inflammatory markers, such as seminal epithelial neutrophil activating peptide-78 and IL-1β. 29 In the present study, we established that the expression levels of PK2 and its receptor PKR1 were increased in varicocele at the protein level, suggesting that the PK2/PKR1 signaling pathway mediated the development of inflammation-related varicocele.…”

Section: Discussionmentioning

confidence: 99%

“…In PK2 knockout mice, gonadotropin-releasing hormone (GnRH) secretory dysfunction results in sexual development and fertility impairment in males, represented by small seminiferous tubules with lumens that lack haploid spermatocytes and spermatids. 10 In our previous studies, PK2 is upregulated in the rat model of lipopolysaccharide (LPS)-induced orchitis 11 and experimental autoimmune orchitis, 12 indicating that PK2 is involved in testicular inflammation. Pro-inflammatory cytokines, such as interleukin-1α (IL-1α), IL-6, and tumor necrosis factor-α (TNF-α), are significantly increased in varicocele, suggesting that a chronic testicular inflammation occurs.…”

Section: Introductionmentioning

confidence: 97%

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Prokineticin 2 overexpression induces spermatocyte apoptosis in varicocele in rats

Liu

Zhou

et al. 2020

Asian J Androl

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Varicocele is one of the most important causes of male infertility, as this condition leads to a decline in sperm quality. It is generally believed that the presence of varicocele induces an increase in reactive oxygen species levels, leading to oxidative stress and sperm apoptosis; however, the specific pathogenic mechanisms affecting spermatogenesis remain elusive. Prokineticin 2 (PK2), a secretory protein, is associated with multiple biological processes, including cell migration, proliferation, and apoptosis. In the testis, PK2 is expressed in spermatocytes under normal physiological conditions. To investigate the role of PK2 in varicocele, a rat varicocele model was established to locate and quantify the expression of PK2 and its receptor, prokineticin receptor 1 (PKR1), by immunohistochemistry and quantitative real-time PCR assays (qPCR). Moreover, H 2 O 2 was applied to mimic the oxidative stress state of varicocele through coculturing with a spermatocyte-derived cell line (GC-2) in vitro , and the apoptosis rate was detected by flow cytometry. Here, we illustrated that the expression levels of PK2 and PKR1 were upregulated in the spermatocytes of the rat model. Administration of H 2 O 2 stimulated the overexpression of PK2 in GC-2. Transfection of recombinant pCMV-HA-PK2 into GC-2 cells promoted apoptosis by upregulating cleaved-caspase-3, caspase-8, and B cell lymphoma 2-associated X; downregulating B cell lymphoma 2; and promoting the accumulation of intracellular calcium. Overall, we revealed that the varicocele-induced oxidative stress stimulated the overexpression of PK2, leading to apoptosis of spermatocytes. Our study provides new insight into the mechanisms underlying oxidative stress-associated male infertility and suggests a novel therapeutic target for male infertility.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Prokineticin 2 overexpression induces spermatocyte apoptosis in varicocele in rats

Liu

Zhou

et al. 2020

Asian J Androl

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“…PK2 exerts chemokine function by binding with cognate G-protein-linked receptors [ 8 ] and is involved in multiple physiological and pathological processes, including reproduction, angiogenesis, and neurogenesis [ 35 – 38 ]. PK2 also participates in inflammation and plays an important role in inducing macrophage infiltration and proinflammatory cytokine release [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

“…PK2 also participates in inflammation and plays an important role in inducing macrophage infiltration and proinflammatory cytokine release [ 39 ]. Moreover, PK2 is highly expressed in mammalian testes [ 40 ] and the PK2/PKR1 pathway contributes to the development of LPS-induced orchitis [ 7 ] and experimental autoimmune orchitis [ 8 ]. Here, the expressions of PK2 and PKR1, as well as IL-1 β , IL-6, and TNF- α , increased after LPS injection, which is consistent with the fact that PK2 enhances the LPS-induced production of proinflammatory cytokines [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

“…Oxidative stress and reactive oxygen species (ROS), which are majorly sourced from macrophages [5], may be the major contributory factors leading to testicular cell apoptosis and acute inflammation of testes [6]. Additionally, it has been shown that the PK2/PKR1 pathway contributes to the development of testicular inflammation [7][8][9]. Hence, treatment strategies for orchitis should focus on the balance of inflammatory cytokines, removal of oxidative and apoptotic injury, and regulation of the PK2/PKR1 pathway.…”

Section: Introductionmentioning

confidence: 99%

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Methane Ameliorates Lipopolysaccharide-Induced Acute Orchitis by Anti-inflammatory, Antioxidative, and Antiapoptotic Effects via Regulation of the PK2/PKR1 Pathway

Huang¹,

Zhang

Sun³

et al. 2020

Oxidative Medicine and Cellular Longevity

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Objective. The present study is aimed at investigating the anti-inflammatory, antioxidative, and antiapoptotic effects of methane on lipopolysaccharide- (LPS-) induced acute orchitis and its potential mechanisms. Methods. Adult male rats were intraperitoneally (i.p.) injected with methane-rich saline (MS, 20 mL/kg) following LPS (5 mg/kg, i.p.). The survival rate was assessed every 12 h until 72 h after LPS induction, and surviving rats were sacrificed for further detection. The wet/dry (W/D) ratio was determined, and testicular damage was histologically assessed. Inflammatory cytokines in the testes and serum, including interleukin-1β (IL-1β), IL-6, IL-10, and tumor necrosis factor-α (TNF-α), were measured using ELISA and RT-qPCR. Oxidative stress was evaluated by the level of superoxide dismutase (SOD) and malondialdehyde (MDA). Testicular apoptosis was detected via TUNEL staining. The expression of prokineticin 2 (PK2)/prokineticin receptor 1 (PKR1) was also analyzed using RT-qPCR, western blotting, and immunohistochemistry. Results. It was found that methane significantly prolonged rat survival, decreased the W/D ratio, alleviated LPS-induced histological changes, and reduced apoptotic cells in the testes. Additionally, methane suppressed and promoted the production of pro- and anti-inflammatory cytokines, respectively. Furthermore, methane significantly increased SOD levels, decreased MDA levels, and decreased testicular expression of PK2 and PKR1. Therefore, methane exerts therapeutic effects on acute orchitis and might be a new and convenient strategy for the treatment of inflammation-related testicular diseases.

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Matrine alleviates spatial learning and memory impairment in diabetic mice by inhibiting endoplasmic reticulum stress and through modulation of PK2/PKRs pathway

Zhang

Liao

et al. 2022

Neurochemistry International

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Effects of prokineticin 2 on testicular inflammation in rats

Abstract: This finding demonstrated that the PK2/PKR1 signals may have an essential role in the regulation of testicular inflammation through iNOS. PK2 interference may represent a novel and promising therapeutic strategy for the clinical management of orchitis.

Cited by 9 publications

References 32 publications

Prokineticin 2 overexpression induces spermatocyte apoptosis in varicocele in rats

Prokineticin 2 overexpression induces spermatocyte apoptosis in varicocele in rats

Methane Ameliorates Lipopolysaccharide-Induced Acute Orchitis by Anti-inflammatory, Antioxidative, and Antiapoptotic Effects via Regulation of the PK2/PKR1 Pathway

Matrine alleviates spatial learning and memory impairment in diabetic mice by inhibiting endoplasmic reticulum stress and through modulation of PK2/PKRs pathway

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