Abstract
Objective The aim of this study was to investigate whether tissue kallikrein (KLK1) can protect the prostate from inflammatory damage and the mechanism involved in it. Methods A total of 50 male Wistar rats were used in this study. Initially, 20 rats were sacrificed to obtain the prostate antigen to induce experimental autoimmune prostatitis (EAP), and the remaining 30 rats were randomly divided into 5 experimental groups (normal control group (NC group), NC+KLK1 group (NCK group), EAP group, EAP+KLK1 group (EAPK group), and EAP+KLK1+HOE140 group (EAPKH group); n = 6). It should be explained that KLK1 mainly exerts its biological effects through bradykinin, and HOE140 is a potent and selective bradykinin receptor B2 (BDKRB2) antagonist. EAP was induced by intradermal injection of 15 mg/ml prostate antigen and complete Freund's adjuvant on days 0, 14, and 28. KLK1 was injected via tail vein at a dose of 1.5 × 10−3 PAN U/kg once a day, and HOE140 was administered by intraperitoneal injection at 20 μg/kg once every two days. Rats were sacrificed on day 42. The RNA and protein of the rat prostate were extracted to analyze the expression differences of KLK1, as well as the inflammation-, fibrosis-, and oxidative stress-related genes. The inflammatory cell infiltration and microvessel density of the prostate were also analyzed by pathological examination. In addition, pathological analysis was performed on prostate samples from patients undergoing benign prostate hyperplasia (BPH) surgery. Results The expression of KLK1 in the prostate decreased in the EAP group as well as BPH patients with obvious inflammation. KLK1 administration significantly inhibited inflammatory cell infiltration and reduced the production of inflammatory cytokines in the EAPK group. Prostate samples from the EAP group showed increased infiltration of T cells and macrophages, as well as gland atrophy, hypoxia, fibrosis, and angiogenesis. KLK1 administration upregulated endothelial nitric oxide synthase (eNOS) expression and suppressed oxidative stress, as well as transforming growth factor β1 (TGF-β) signaling pathways and the proangiogenic vascular endothelial growth factor (VEGF) in the EAPK group. However, in the EAPKH group in which HOE140 blocked BDKRB2, the beneficial effects of KLK1 were all cancelled. In addition, KLK1 intervention in normal rats had no obvious side effects. Conclusion The KLK1 expression is inhibited in the inflamed prostates of humans and rats. Exogenous KLK1 restored endothelial function via a BDKRB2-dependent way and then played a role in improving microcirculation and exerted anti-inflammatory, antifibrotic, and antioxidative stress effects in the rat chronic-inflamed prostate.
Highlights
benign prostate hyperplasia (BPH) is a common and bothersome benign proliferative disease and has a significant impact on the quality of life for middle-aged and older men
Through the results of H&E sections, we confirmed that the experimental autoimmune prostatitis (EAP) group was successfully induced with chronic prostatitis, which manifested as gland atrophy, thickened smooth muscle, and diffuse infiltration of inflammatory cells (Figure 2(f))
Compared with the NC group, the mRNA and protein expression levels of KLK1 in the prostates of the EAP group were significantly reduced (Figures 2(a)–2(c)). It could be seen from the IHC photos that the expression of KLK1 in prostate epithelial cells in the EAP group was lower than that in the NC group (Figures 2(d) and 2(e)). These results suggested that the expression of KLK1 in the prostate was inhibited during the development of chronic prostatitis
Summary
BPH is a common and bothersome benign proliferative disease and has a significant impact on the quality of life for middle-aged and older men. The prevalence of BPH rises with age. 40% of 50-year-old men and 90% of 90-year-old men suffer BPH [1]. A variety of pathogenic factors have jointly caused the progressive hyperplasia of prostatic glandular epithelial and stromal cells and other pathological changes, which further leads to prostate enlargement and bladder outflow obstruction and eventually leads to LUTS, such as urinary hesitancy, frequency incontinence, pain, and nocturia. We have previously reported the protective effect of KLK1 on the rodent aging prostate [2]. Inflammation is one of the important mechanisms of BPH progression discovered in recent years. We will report the effect of KLK1 on the inflammation mechanism in BPH/LUTS by using an EAP rat model
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