Cellular mechanisms underlying carbon monoxide stimulated anion secretion in rat epididymal epithelium

Peng, Lei; Gao, Dong-Dong; Xu, Jiawen; Xu, Jian-Bang; Ke, Li-Jiao; Qiu, Zhen; Zhu, Yun-Xin; Zhang, Yilin; Zhou, Wen‐Liang

doi:10.1016/j.niox.2020.04.004

Cited by 8 publications

(7 citation statements)

References 51 publications

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“…Under the experimental conditions used by Uc et al (70) and Steidle and Diener (66), it is feasible that the inhibitors DIDS, glibenclamide and NPPB might have decreased short-circuit current (I sc ) by targeting other anion channels, not CFTR. Consistent with this idea, in rat epididymal epithelia, the NPPBand DIDS-sensitive CORM-2-induced increase in I sc was robustly inhibited by chelation of intracellular Ca 2+ with BAPTA-AM, whereas the CFTR inhibitor CFTR inh -172 had little effect (48). These data suggest that in rat epididymal epithelia CORM-2 increases I sc by targeting the Ca 2+ -activated Clchannel TMEM16A (47).…”

Section: Discussionsupporting

confidence: 61%

“…Second, we did not measure CO generation by CORM-2 and CORM-3. However, we used both CO-releasing molecules at concentrations equivalent to those employed in previous studies of CO's action on epithelial anion transport (48,66,70,89) and demonstrated to liberate CO similar to the original descriptions of these agents (CORM-2: 0.7 mole CO per mole CORM-2; CORM-3: 1 mole CO per mole CORM-3) (11,42,89). Although the CO concentration in epithelial cells is difficult to determine (66), these concentrations are similar to those estimated for endogenous CO production by humans under physiological conditions (~18 μmole CO h -1 ) (12,57).…”

Section: Previous Work Has Identified Two General Mechanisms Of Cftr Inhibition: Open-mentioning

confidence: 99%

“…Of note, HO-1 is a modifier gene for Pseudomonas aeruginosa infection in CF (46), while in macrophages ezrin appears to assemble HO-1 and CFTR into a macromolecular signaling complex (15,20). However, the action of CO appears to be tissuespecific, stimulating Clsecretion in the intestine (66,70) and epididymis (48), Na + absorption in the kidney ( 81), but inhibiting ion transport in the lung (2,89). These distinct effects of CO on epithelial ion transport might be explained by differences in the redox status of cells (85).…”

Section: Previous Work Has Identified Two General Mechanisms Of Cftr Inhibition: Open-mentioning

confidence: 99%

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Carbon monoxide-releasing molecules inhibit the cystic fibrosis transmembrane conductance regulator Cl⁻channel

Rodrat

Jantarajit

et al. 2020

American Journal of Physiology-Lung Cellular and Molecular Phys

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The gasotransmitter carbon monoxide (CO) regulates fluid and electrolyte movements across epithelial tissues. However, its action on anion channels is incompletely understood. Here, we investigate the direct action of CO on the cystic fibrosis transmembrane conductance regulator (CFTR) by applying CO-releasing molecules (CORMs) to the intracellular side of excised inside-out membrane patches from cells heterologously expressing wild-type human CFTR. Addition of increasing concentrations of tricarbonyldichlororuthenium (II) dimer (CORM-2) (1 - 300 μM) inhibited CFTR channel activity, whereas the control RuCl3 (100 μM) was without effect. CORM-2 predominantly inhibited CFTR by decreasing the frequency of channel openings and hence, open probability (Po). But, it also reduced current flow through open channels with very fast kinetics, particularly at elevated concentrations. By contrast, the chemically distinct CO-releasing molecule CORM-3 inhibited CFTR by decreasing Po without altering current flow through open channels. Neither depolarizing the membrane voltage nor raising the ATP concentration on the intracellular side of the membrane affected CFTR inhibition by CORM-2. Interestingly, CFTR inhibition by CORM-2, but not by CFTRinh-172, was prevented by prior enhancement of channel activity by the clinically-approved CFTR potentiator ivacaftor. Similarly, when added after CORM-2, ivacaftor completely relieved CFTR inhibition. In conclusion, CORM-2 has complex effects on wild-type human CFTR consistent with allosteric inhibition and open-channel blockade. Inhibition of CFTR by CO-releasing molecules suggests that CO regulates CFTR activity and that the gasotransmitter has tissue-specific effects on epithelial ion transport. The action of ivacaftor on CFTR Cl- channels inhibited by CO potentially expands the drug's clinical utility.

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Section: Discussionsupporting

confidence: 61%

Section: Previous Work Has Identified Two General Mechanisms Of Cftr Inhibition: Open-mentioning

confidence: 99%

Section: Previous Work Has Identified Two General Mechanisms Of Cftr Inhibition: Open-mentioning

confidence: 99%

See 1 more Smart Citation

Carbon monoxide-releasing molecules inhibit the cystic fibrosis transmembrane conductance regulator Cl⁻channel

Rodrat

Jantarajit

et al. 2020

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Epididymis promotes sperm maturation by the secretion of various functional proteins through the epididymal epithelium when post-testis sperm transit from the caput to cauda. 55 Given that PCs are the primary cell type in this epithelium and secrete key molecules, deficiency in sperm function can possibly result from damage to the epididymal PCs. In turn, the epididymal function mainly depends on the integrity of the epididymal and luminal components.…”

Section: Discussionmentioning

confidence: 99%

Sperm immotility is associated with epididymis metabolism disorder in mice under obstructive azoospermia

et al. 2023

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Obstructive azoospermia (OA) accounts for approximately 40% of males who suffer from azoospermia of male infertility. Currently, available treatment for OA consists of reproductive tract surgical reconstruction and sperm retrieval from the testis. However, both treatments result in low fertility compared to normal pregnancy, and the main reason remains largely unknown. Previous studies have shown that the quality of sperm retrieved from OA patients is poor compared with normal adult males but without an in‐depth study. Herein, we generated a mouse OA model with vasectomy to evaluate sperm quality systematically. Our results showed that the testis had normal spermatogenesis but increased apoptotic activity in both OA patients and mice. More importantly, epididymal morphology was abnormal, with swollen epididymal tubules and vacuole‐like principal cells. Especially, sperm retrieved from the epididymis of OA mice showed poor motility and low fertilization ability in vitro. Using mass spectrometry in epididymal fluid, we found differences in the expression of key proteins for sperm maturation, such as Angiotensinogen (AGT), rhophilin‐associated tail protein 1 (ROPN1), NPC intracellular cholesterol transporter 2 (NPC2), and prominin 1 (PROM1). Furthermore, our results demonstrated that AGT, secreted by epididymal principal cells, could regulate sperm motility by managing PKCα expression to modify sperm phosphorylation. In conclusion, our data evaluate sperm quality systematically in OA mice and contribute to the understanding between the sperm and epididymis, which may provide novel insight into treating male infertility.

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“…The Ussing chamber experiments were performed as described previously [30]. In Brief, the monolayers were vertically clamped in the Ussing chamber, with a perfusion system to maintain the system at 32 • C. The voltage-clamp amplifier (VCC MC6, Physiologic Instruments, San Diego, CA, USA) employed to short-circuit the monolayer, and a signal collection and analysis system (BL-420E+, Chengdu Technology & Market, Chengdu, China) used to obtain real-time I SC data.…”

Section: Measurement Of the I Scmentioning

confidence: 99%

Aerobic exercises regulate the epididymal anion homeostasis of high-fat diet-induced obese rats through TRPA1-mediated Cl− and HCO3− secretion

Gao

Ding

Deng

et al. 2023

Biology of Reproduction

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Aerobic exercises could improve the sperm motility of obese individuals. However, the underlying mechanism has not been fully elucidated, especially the possible involvement of the epididymis in which sperm acquire their fertilizing capacity. This study aims to investigate the benefit effect of aerobic exercises on the epididymal luminal milieu of obese rats. Sprague–Dawley male rats were fed on a normal or high-fat diet (HFD) for ten weeks and then subjected to aerobic exercises for 12 weeks. We verified that TRPA1 was located in the epididymal epithelium. Notably, aerobic exercises reversed the down-regulated TRPA1 in the epididymis of HFD-induced obese rats, thus improving sperm fertilizing capacity and Cl− concentration in epididymal milieu. Ussing chamber experiments showed that cinnamaldehyd (CIN), agonist of TRPA1, stimulated an increase of the short-circuit current (ISC) in rat cauda epididymal epithelium, which was subsequently abolished by removing the ambient Cl− and HCO3−. In vivo data revealed that aerobic exercises increased the CIN-stimulated Cl− secretion rate of epididymal epithelium in obese rats. Pharmacological experiments revealed that blocking cystic fibrosis transmembrane regulator (CFTR) and Ca2+-activated Cl− channel (CaCC) suppressed the CIN-stimulated anion secretion. Moreover, CIN application in rat cauda epididymal epithelial cells elevated intracellular Ca2+ level, and thus activate CACC. Interfering with the PGHS2-PGE2-EP2/EP4-cAMP pathway suppressed CFTR-mediated anion secretion. This study demonstrates that TRPA1 activation can stimulate anion secretion via CFTR and CaCC, which potentially forming an appropriate microenvironment essential for sperm maturation, and aerobic exercises can reverse the down-regulation of TRPA1 in the epididymal epithelium of obese rats.

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Cellular mechanisms underlying carbon monoxide stimulated anion secretion in rat epididymal epithelium

Cited by 8 publications

References 51 publications

Carbon monoxide-releasing molecules inhibit the cystic fibrosis transmembrane conductance regulator Cl⁻channel

Carbon monoxide-releasing molecules inhibit the cystic fibrosis transmembrane conductance regulator Cl⁻channel

Sperm immotility is associated with epididymis metabolism disorder in mice under obstructive azoospermia

Aerobic exercises regulate the epididymal anion homeostasis of high-fat diet-induced obese rats through TRPA1-mediated Cl− and HCO3− secretion

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Cellular mechanisms underlying carbon monoxide stimulated anion secretion in rat epididymal epithelium

Cited by 8 publications

References 51 publications

Carbon monoxide-releasing molecules inhibit the cystic fibrosis transmembrane conductance regulator Cl−channel

Carbon monoxide-releasing molecules inhibit the cystic fibrosis transmembrane conductance regulator Cl−channel

Sperm immotility is associated with epididymis metabolism disorder in mice under obstructive azoospermia

Aerobic exercises regulate the epididymal anion homeostasis of high-fat diet-induced obese rats through TRPA1-mediated Cl− and HCO3− secretion

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Product

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Carbon monoxide-releasing molecules inhibit the cystic fibrosis transmembrane conductance regulator Cl⁻channel

Carbon monoxide-releasing molecules inhibit the cystic fibrosis transmembrane conductance regulator Cl⁻channel