Transforming Growth Factor Beta 1 Induces Tight Junction Disruptions and Loss of Transepithelial Resistance Across Porcine Vas Deferens Epithelial Cells1

Abstract

Epithelial cells lining the male excurrent duct contribute to male fertility by employing a number of physiological mechanisms that generate a luminal microenvironment conducive to spermatozoa maturation and storage. Among these mechanisms, male duct epithelia establish intercellular tight junctions that constitute a barrier to paracellular diffusion of water, solutes, large molecules, and cells. Mechanisms regulating the male duct epithelial barrier remain unidentified. Transforming growth factor beta (TGFB) is a regulatory cytokine present in high concentrations in human semen. This study examined whether TGFB has any effects on epithelial function exhibited by primary cultures of porcine vas deferens epithelia. TGFB1 exposure caused a 70%-99% decrease in basal transepithelial electrical resistance (R(TE), a sensitive indicator of barrier integrity), while a significant decrease in anion secretory response to forskolin was detected at the highest levels of TGFB1 exposure employed. SB431542, a selective TGFB receptor I (TGFBR1) inhibitor, prevented decreases in barrier function. Results also demonstrated that TGFB1 exposure modifies the distribution pattern of tight junction proteins occludin and claudin 7. TGFBR1 is localized at the apical border of the native porcine vas deferens epithelium. Pharmacological inhibition of mitogen-activated protein kinase (MAPK) 11 (also known as p38-MAPK) did not alter the effect of TGFB1 on R(TE) significantly. These data suggest that epithelia lining the vas deferens are subject to disruptions in the physical barrier if active TGFB becomes bioavailable in the luminal fluid, which might be expected to compromise fertility.

Protein Network Analysis and Functional Studies of Calcium Oxalate Crystal‐Induced Cytotoxicity in Renal Tubular Epithelial Cells

“…Finally, the network involving cellular junction complex and integrity was examined. Interestingly, we found the increase in TGFBR1 that has been previously reported to induce tight junction dissociation . Such increase was consistent with the functional data demonstrating disruption of ZO‐1 expression and defective TER (Figure ).…”

TGF-Beta Downregulation of Distinct Chloride Channels in Cystic Fibrosis-Affected Epithelia

“…The results confirm reports by Howe and colleagues [25] describing downregulation of CFTR by TGF-beta in T84 cells. Similar findings in the porcine vas deferens have been reported by Pierucci-Alves and colleagues [39] , and both of these studies identified p38 MAPK as a contributor to TGF-beta inhibition of CFTR. Our data also confirm recent reports in HAECs [26] , [37] , including downregulation of wtCFTR and F50del CFTR currents and expression produced by VX-809.…”

Vectorial secretion of CTGF as a cell-type specific response to LPA and TGF-β in human tubular epithelial cells

“…Even with certain MDCK cells (subtype MDCKII) apical activation by TGF-β has been reported [43]. Apical localization of TGF-β receptor I was also reported in porcine vas deferens epithelium [44]. In the kidney, Wang et al had provided evidence for apical expression of TGF-β receptors in a subset of rat cortical collecting duct cells, and showed in vitro reactivity of mouse proximal tubular cells and renal inner medullary cell lines (mIMCD-3 cells) upon apical stimulation with TGF-β [45].…”