Urethral dysfunction in a rat model of chemically induced prostatic inflammation: potential involvement of the MRP5 pump

Author(s)

Alexandre, Eduardo C. ^{[1, 2]} ; Cao, Nailong ^[2] ; Mizoguchi, Shinsuke ^[2] ; Saito, Tetsuichi ^[2] ; Kurobe, Masahiro ^[2] ; Gotoh, Daisuke ^[2] ; Okorie, Meri ^[2] ; Igarashi, Taro ^[2] ; Antunes, Edson ^[1] ; Yoshimura, Naoki ^[2]

Affiliation

^[1] Univ Estadual Campinas, Fac Med Sci, Dept Pharmacol, Campinas, SP - Brazil

^[2] Univ Pittsburgh, Dept Urol, Sch Med, Pittsburgh, PA 15213 - USA

• Document type: Journal article
• Source: AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY; v. 318, n. 3, p. F754-F762, MAR 2020.
• Web of Science Citations: 0

Abstract

Prostate inflammation (P1) is a clinical condition associated with infection and/or inflammation of the prostate. It is a common disease frequently associated to lower urinary tract (LUT) symptoms. The urethra is an understudied structure in the LUT and plays a fundamental role in the urinary cycle. Here, we proposed to evaluate the effect of PI on the urethra tissue. Male Sprague-Dawley rats were used, and PI was induced by formalin injection into the ventral lobes of the prostate. The pelvic urethra at the prostatic level was harvested for histological analysis. contraction (electrical field stimulation and phenylephrine), and relaxation (sodium nitroprusside/MK-571) experiments. Various gene targets {[}cytochrome c oxidase subunit 2. transforming growth factor-beta(1), interleukin-1 beta, hypoxia-inducible factor-l alpha, alpha(1A)-adrenoceptor, inositol 1,4,5-trisphosphate receptor type 1. voltage-gated Ca2+ channel subunit-alpha(1D), neuronal nitric oxide synthase, soluble guanylyl cyclase, phosphodiesterase 5A. protein kinase CGMP-dependent 1. and multidrug resistance-associated protein 5 (MRP5; ATP-binding cassette subfamily C member 5)] were quantified, and cGMP levels were measured. No histological changes were detected, and functional assays revealed decreased contraction and increased relaxation of urethras from the PI group. The addition of MK-571 to functional assays increased urethral relaxation. Genes associated with inflammation were upregulated in urethras from the PI group, such as cytochrome oxidase c subunit 2, transforming growth factor-beta(1), interleukin-1 beta, and hypoxia-inducible factor-1 alpha. We also found increased expression of L-type Ca2+ channels and the neuronal nitric oxide synthase enzyme and decreased expression of the MRP5 pump. Finally, cGMP production was enhanced in urethral tissue of PI animals. The results indicate that PI is associated with proinflammatory gene expression in the urethra without histologically evident inflammation and that PI produces a dysfunctional urethra and MRP5 pump downregulation, which results in cGMP accumulation inside the cell. These findings would help to better understand LUT dysfunctions associated with PI and the role of MRP pumps in the control of LUT function. (AU)

• FAPESP's process: 17/15175-1 - Modulation of soluble guanylate cyclase and the intracellular levels of cyclic nucleotides in the lower urinary tract and prostate
• Grantee: Edson Antunes
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 18/03625-5 - The Influence of Prostatitis in The Rat Urethra Smooth Muscle: Functional and Molecular Approaches
• Grantee: Eduardo Costa Alexandre
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor