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Reciprocal regulation of cyclic GMP content by cyclic GMP-phosphodiesterase and guanylate cyclase in SHR with CsA-induced nephrotoxicity.

ABSTRACT: 1. The effect of the immunosuppressant drug, cyclosporin A (CsA), on the nitric oxide (NO)-cyclic GMP pathway was examined in spontaneous hypertensive rats (SHR). 2. CsA (50 mg kg(-1)) treatment for 14 days induced typical CsA nephrotoxicity, which was characterized by morphological changes in the glomerulus and proximal tubule as well as an abnormality of creatinine clearance, FENa and BUN. 3. CsA significantly decreased both NOS activity in the kidney and NOx contents in urine, but significantly increased cyclic GMP content in the kidney. 4. A marked change in two kinds of enzyme, which contribute towards the increase in cyclic GMP in tissue, namely, a decrease in cyclic GMP-phosphodiesterase activity and increase in guanylate cyclase activity, was observed in the kidney treated with CsA. 5. In the isolated perfused kidney, a decreased in perfusion pressure induced by SNP in the kidney isolated from CsA group was significantly greater than that of control. 6. There seem to exist a reciprocal mechanism to maintain cyclic GMP content via both a decrease in cyclic GMP degradation and an increase in synthesis of cyclic GMP in the kidney treated with CsA. This mechanism is likely to be playing an important role to regulate the homeostasis in the kidney with CsA nephrotoxicity.

SUBMITTER: Hosogai N

PROVIDER: S-EPMC1573030 | biostudies-other | 2001 Nov

REPOSITORIES: biostudies-other

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Project description:Cyclic dimeric GMP (c-di-GMP) is a universal second messenger in bacteria. A large number of c-di-GMP-related diguanylate cyclases (DGCs), phosphodiesterases (PDEs), and effectors are responsible for the complexity and dynamics of c-di-GMP signaling. Some of these components employ various methods to avoid undesired cross talk to maintain signaling specificity. The synthesis of the antibiotic HSAF (heat-stable antifungal factor) in Lysobacter enzymogenes is regulated by a specific c-di-GMP signaling pathway that includes a PDE, LchP, and a c-di-GMP effector, Clp (also a transcriptional regulator). In the present study, from among 19 DGCs, we identified a diguanylate cyclase, LchD, that participates in this pathway. Subsequent investigation indicates that LchD and LchP physically interact and that the catalytic center of LchD is required for both the formation of the LchD-LchP complex and HSAF production. All the detected phenotypes support that LchD and LchP display local c-di-GMP signaling to regulate HSAF biosynthesis. Although direct evidence is lacking, our investigation, which shows that the interaction between a DGC and a PDE maintains the specificity of c-di-GMP signaling, suggests the possibility of the existence of local c-di-GMP pools in bacteria. IMPORTANCE Cyclic dimeric GMP (c-di-GMP) is a universal second messenger in bacteria. The signaling of c-di-GMP is complex and dynamic, and it is mediated by a large number of components, including c-di-GMP synthases (diguanylate cyclases [DGCs]), c-di-GMP-degrading enzymes (phosphodiesterases [PDEs]), and c-di-GMP effectors. These components deploy various methods to avoid undesired cross talk to maintain signaling specificity. In the present study, we identified a DGC that interacted with a PDE to specifically regulate antibiotic biosynthesis in L. enzymogenes. We provide direct evidence to show that the DGC and PDE form a complex and also indirect evidence to argue that they may balance a local c-di-GMP pool to control antibiotic production. These results represent an important finding regarding the mechanism of a DGC and PDE pair to control the expression of specific c-di-GMP signaling pathways.

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Reciprocal regulation of cyclic GMP content by cyclic GMP-phosphodiesterase and guanylate cyclase in SHR with CsA-induced nephrotoxicity.

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