ABSTRACT
Emerging evidence indicates that aldosterone and mineralocorticoid receptors (MRs) are associated with the pathogenesis of erectile dysfunction. However, the molecular mechanisms remain largely unknown. In this study, freshly isolated penile corpus cavernosum tissue from rats was treated with aldosterone, with or without MRs inhibitors. Nuclear factor (NF)-kappa B (NF-κB) activity was evaluated by real-time quantitative PCR, luciferase assay, and immunoblot. The results demonstrated that mRNA levels of the NF-κB target genes, including inhibitor of NF-κB alpha (IκB-α), NF-κB1, tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6), were higher after aldosterone treatment. Accordingly, phosphorylation of p65/RelA, IκB-α, and inhibitor of NF-κB kinase-ß was markedly increased by aldosterone. Furthermore, knockdown of MRs prevented activation of the NF-κB canonical pathway by aldosterone. Consistent with this finding, ectopic overexpression of MRs enhanced the transcriptional activation of NF-κB by aldosterone. More importantly, the MRs antagonist, spironolactone blocked aldosterone-mediated activation of the canonical NF-κB pathway. In conclusion, aldosterone has an inflammatory effect in the corpus cavernosum penis, inducing NF-κB activation via an MRs-dependent pathway, which may be prevented by selective MRs antagonists. These data reveal the possible role of aldosterone in erectile dysfunction as well as its potential as a novel pharmacologic target for treatment.
Subject(s)
Aldosterone/pharmacology , Cytokines/biosynthesis , NF-kappa B/agonists , Penis/metabolism , Signal Transduction/drug effects , Animals , Gene Knockdown Techniques , I-kappa B Kinase/antagonists & inhibitors , Interleukin-6/biosynthesis , Interleukin-6/genetics , Male , Mineralocorticoid Receptor Antagonists/pharmacology , NF-kappa B/genetics , Penis/drug effects , Protein Serine-Threonine Kinases/antagonists & inhibitors , RNA, Messenger/biosynthesis , Rats , Rats, Inbred WKY , Receptors, Mineralocorticoid/biosynthesis , Receptors, Mineralocorticoid/genetics , Spironolactone/pharmacology , Transcriptional Activation , Tumor Necrosis Factor-alpha/biosynthesis , NF-kappaB-Inducing KinaseABSTRACT
BACKGROUND: We aimed to examine whether proinflammatory cytokines participated in prostate cancer (PCa) development and progression promoted by high-fat diet (HFD). METHODS: TRAMP (transgenic adenocarcinoma mouse prostate) mice were randomly divided into two groups: normal diet group and HFD group. Mortality rate and tumor formation rate were examined. TRAMP mice were sacrificed and sampled on the 20th, 24th, and 28th week, respectively. Levels of proinflammatory cytokines, including IL-1α, IL-1ß, IL-6, and TNF-α, were tested by FlowCytomix. Prostate tissue of TRAMP mice was used for histology study. RESULTS: A total of 13 deaths of TRAMP mice were observed, among which 3 (8.33%) were from the normal diet group and 10 (27.78%) from the HFD group. The mortality rate of TRAMP mice from HFD group was significantly higher than that of normal diet group (P = 0.032). Tumor formation rate at 20th week of age of HFD group was significantly higher than that of normal diet group (P = 0.045). Proinflammatory cytokines levels, including IL-1α, IL-1ß, IL-6, and TNF-α, were significantly higher in HFD TRAMP mice. CONCLUSIONS: HFD could promote TRAMP mouse PCa development and progression with elevated proinflammatory cytokines levels. Proinflammatory cytokines could contribute to PCa development and progression promoted by HFD.
Subject(s)
Diet, High-Fat/adverse effects , Inflammation/metabolism , Inflammation/pathology , Interleukins/metabolism , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Tumor Necrosis Factor-alpha/metabolism , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Animals , Disease Progression , Male , Mice , Mice, Transgenic , Prostate/metabolism , Prostate/pathologyABSTRACT
To explore the rationale for renal-sparing surgery as an alternative method to radical nephrectomy in the treatment of renal cell carcinoma (RCC), we analyzed clinical data from 94 patients diagnosed as having RCC. They were divided into 3 groups based on the maximum diameter of their tumor specimens. Group A had tumors size ranging from 0 to 4 cm, group B had tumors size ranging from 4 to 7 cm, and group C had tumors size greater than 7 cm. Tissue samples (5 cm) were taken from the upper pole side, lower pole side, and renal pelvic side of the tumor pseudocapsule; if the tumor was located on 1 pole of the kidney, samples were collected from 2 directions. The specimens were then embedded in paraffin and cut serially at segments 0 to 1, 1 to 3, and 3 to 5 cm. Staining with hematoxylin and eosin, anti-pancytokeratin, and vimentin was performed to determine tumor type and tumor infiltration. From the 94 patients analyzed, 2 patients in group A had RCC metastasis within 1 cm of tissue around the pseudocapsule, and 4 patients in groups B and C had lymph node metastasis without metastasis in the tissue 1 cm outside the pseudocapsule in all 3 directions described. There was no statistical significant difference found between the incidence of local metastasis of the various tumor sizes, suggesting that local metastasis of RCC is not associated with the size of the tumor. Based on the observation that incidences of local metastasis were low in early-stage RCC, we came to the conclusion that pseudocapsule of RCC tumor might have growth-limiting effect on the tumor enclosed. It is theoretically a safer and better surgical option for patients with RCC with a smaller size of tumor and indications for radical nephrectomy to undergo renal-sparing surgery with an excision margin of 1 cm of normal tissue around the pseudocapsule of the tumor.
