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Nitric Oxide-Mediated Regulation of Connexin43 Expression and Gap Junctional Intercellular Communication in Mesangial Cells

Jian Yao^*, Nobuhiko Hiramatsu^*, Ying Zhu, Tetsuo Morioka, Masayuki Takeda, Takashi Oite and Masanori Kitamura^*

^* Departments of Molecular Signaling and Urology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Tamaho, Yamanashi, Japan; and the Department of Cellular Physiology, Institute of Nephrology, Niigata University, Niigata, Japan

Address correspondence to: Dr. Jian Yao, Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Tamaho, Yamanashi 409-3898, Japan. Phone/Fax: +81-55-273-8074; yao{at}yamanashi.ac.jp

This study investigated a potential role of nitric oxide (NO) in the regulation of gap junctional intercellular communication (GJIC). Incubation of mesangial cells (MC) with NO donor S-nitroso-N-acetylpenicillamine (SNAP) enhanced both basal and 8-bromo-cAMP–stimulated GJIC as well as expression of gap junction protein connexin43 (Cx43). This potentiating action of SNAP on Cx43 expression was mimicked by two other NO donors and significantly blocked by soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-]quinoxalin-1–1. Guanosine 3',5'-cyclic monophosphate (cGMP) analogue 8-bromo-cGMP exerted an effect similar to NO, whereas another cGMP analogue, 8-pCPT-cGMP, which selectively activates cGMP-dependent kinase without affecting cGMP-inhibited phosphodiesterase (PDE3), had no effect. Moreover, the synergistic action of NO on Cx43 expression was completely prevented by protein kinase A inhibitor H89 but not by cGMP-dependent kinase inhibitor Rp-8-Br-PET-cGMP. These results suggested a possible involvement of NO-cAMP interaction via cGMP-mediated inhibition of PDE3. Indeed, PDE3 inhibitor cilostamide caused potentiation of 8-bromo-cAMP–elicited elevations of Cx43 expression that is similar to the effect of SNAP, and an elevation of intracellular cAMP was detected in SNAP-treated cells. With the use of genetically engineered reporter MC that express secreted alkaline phosphatase under the control of the cAMP response element, significant potentiation of cAMP-elicited activation of cAMP response element by SNAP was found. This effect was abrogated in the presence of PDE3 inhibitor cilostamide. Taken together, the results suggest that NO is involved in the control of GJIC and Cx43 expression. This effect of NO is due to activation of protein kinase A via cGMP-dependent inhibition of PDE3 activity.

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