Formation of reactive oxygen metabolites in glomeruli is suppressed by inhibition of cAMP phosphodiesterase isozyme type IV

Claudia C S Chini, Eduardo Nunes Chini, Josie M. Williams, Karel Matoušovic, Thomas P. Dousa

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Several independent studies indicate that synthetic inhibitors of cyclic-3',5'-nucleotide phosphodiesterase (PDE) isozymes, especially inhibitors of PDE-IV, are potent agents which suppress generation of reactive oxygen metabolites (ROM) by NADPH oxidase in leukocytes. Recent studies also show that NADPH oxidase is present in all cell types populating glomeruli. In view of this, we investigated PDE isozymes and their relation to ROM in isolated rat glomeruli. Glomeruli have the capacity to hydrolyze cAMP by isozymes PDE-II, PDE-III and PDE-IV, whereas cGMP is hydrolyzed by PDE-I and PDE-V. Inhibitor of PDE-IV rolipram inhibited significantly (cca 40 to 50%) ROM generation in response to stimulation by phorbol myristate acetate (PMA). Inhibitor of PDE-III cilostamide had only minor suppressive effects and inhibitors of other PDE isozymes did not influence ROM generation. Rolipram (3 μM) suppressed ROM generation without detectable increase in cAMP content. Incubation of glomeruli with forskolin, which increased cAMP content in glomeruli tenfold, inhibited ROM generation to a similar degree as rolipram. The suppression of ROM generation by rolipram was prevented by Rp-cAMPS, a specific inhibitor of protein kinase A (PKA) activity. Further, incubation of glomeruli with rolipram elicited marked in situ activation of PKA (+100%), as documented by increase in the (-cAMP/+cAMP) PKA activity ratio. We suggest that selective inhibitor of PDE-IV rolipram acted via the cAMP-signaling pathway and suppressed ROM generation possibly via phosphorylating ras-type GTP-binding protein component of NADPH oxidase and thereby blocking assembly of functional NADPH oxidase complex. Results also suggest that ROM burst in glomeruli is modulated by a distinct cAMP-signaling pathway which is controlled by PDE-IV. We surmise that inhibitors of PDE-IV might be effective agents for suppression of ROM generation in glomeruli in vivo and attenuation of glomerular injury.

Original languageEnglish (US)
Pages (from-to)28-36
Number of pages9
JournalKidney International
Volume46
Issue number1
StatePublished - Jul 1994

Fingerprint

Type 4 Cyclic Nucleotide Phosphodiesterase
Isoenzymes
Rolipram
Oxygen
NADPH Oxidase
Cyclic AMP-Dependent Protein Kinases
Type 3 Cyclic Nucleotide Phosphodiesterases
spleen exonuclease
Phosphodiesterase Inhibitors
3',5'-Cyclic-AMP Phosphodiesterases
Phosphodiesterase I
Type 5 Cyclic Nucleotide Phosphodiesterases
Phosphoric Diester Hydrolases
Tetradecanoylphorbol Acetate
Colforsin
GTP-Binding Proteins
Leukocytes

ASJC Scopus subject areas

  • Nephrology

Cite this

Formation of reactive oxygen metabolites in glomeruli is suppressed by inhibition of cAMP phosphodiesterase isozyme type IV. / Chini, Claudia C S; Chini, Eduardo Nunes; Williams, Josie M.; Matoušovic, Karel; Dousa, Thomas P.

In: Kidney International, Vol. 46, No. 1, 07.1994, p. 28-36.

Research output: Contribution to journalArticle

Chini, Claudia C S ; Chini, Eduardo Nunes ; Williams, Josie M. ; Matoušovic, Karel ; Dousa, Thomas P. / Formation of reactive oxygen metabolites in glomeruli is suppressed by inhibition of cAMP phosphodiesterase isozyme type IV. In: Kidney International. 1994 ; Vol. 46, No. 1. pp. 28-36.
@article{51f8d10a3f734d25b889002821e4f5dc,
title = "Formation of reactive oxygen metabolites in glomeruli is suppressed by inhibition of cAMP phosphodiesterase isozyme type IV",
abstract = "Several independent studies indicate that synthetic inhibitors of cyclic-3',5'-nucleotide phosphodiesterase (PDE) isozymes, especially inhibitors of PDE-IV, are potent agents which suppress generation of reactive oxygen metabolites (ROM) by NADPH oxidase in leukocytes. Recent studies also show that NADPH oxidase is present in all cell types populating glomeruli. In view of this, we investigated PDE isozymes and their relation to ROM in isolated rat glomeruli. Glomeruli have the capacity to hydrolyze cAMP by isozymes PDE-II, PDE-III and PDE-IV, whereas cGMP is hydrolyzed by PDE-I and PDE-V. Inhibitor of PDE-IV rolipram inhibited significantly (cca 40 to 50{\%}) ROM generation in response to stimulation by phorbol myristate acetate (PMA). Inhibitor of PDE-III cilostamide had only minor suppressive effects and inhibitors of other PDE isozymes did not influence ROM generation. Rolipram (3 μM) suppressed ROM generation without detectable increase in cAMP content. Incubation of glomeruli with forskolin, which increased cAMP content in glomeruli tenfold, inhibited ROM generation to a similar degree as rolipram. The suppression of ROM generation by rolipram was prevented by Rp-cAMPS, a specific inhibitor of protein kinase A (PKA) activity. Further, incubation of glomeruli with rolipram elicited marked in situ activation of PKA (+100{\%}), as documented by increase in the (-cAMP/+cAMP) PKA activity ratio. We suggest that selective inhibitor of PDE-IV rolipram acted via the cAMP-signaling pathway and suppressed ROM generation possibly via phosphorylating ras-type GTP-binding protein component of NADPH oxidase and thereby blocking assembly of functional NADPH oxidase complex. Results also suggest that ROM burst in glomeruli is modulated by a distinct cAMP-signaling pathway which is controlled by PDE-IV. We surmise that inhibitors of PDE-IV might be effective agents for suppression of ROM generation in glomeruli in vivo and attenuation of glomerular injury.",
author = "Chini, {Claudia C S} and Chini, {Eduardo Nunes} and Williams, {Josie M.} and Karel Matoušovic and Dousa, {Thomas P.}",
year = "1994",
month = "7",
language = "English (US)",
volume = "46",
pages = "28--36",
journal = "Kidney International",
issn = "0085-2538",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Formation of reactive oxygen metabolites in glomeruli is suppressed by inhibition of cAMP phosphodiesterase isozyme type IV

AU - Chini, Claudia C S

AU - Chini, Eduardo Nunes

AU - Williams, Josie M.

AU - Matoušovic, Karel

AU - Dousa, Thomas P.

PY - 1994/7

Y1 - 1994/7

N2 - Several independent studies indicate that synthetic inhibitors of cyclic-3',5'-nucleotide phosphodiesterase (PDE) isozymes, especially inhibitors of PDE-IV, are potent agents which suppress generation of reactive oxygen metabolites (ROM) by NADPH oxidase in leukocytes. Recent studies also show that NADPH oxidase is present in all cell types populating glomeruli. In view of this, we investigated PDE isozymes and their relation to ROM in isolated rat glomeruli. Glomeruli have the capacity to hydrolyze cAMP by isozymes PDE-II, PDE-III and PDE-IV, whereas cGMP is hydrolyzed by PDE-I and PDE-V. Inhibitor of PDE-IV rolipram inhibited significantly (cca 40 to 50%) ROM generation in response to stimulation by phorbol myristate acetate (PMA). Inhibitor of PDE-III cilostamide had only minor suppressive effects and inhibitors of other PDE isozymes did not influence ROM generation. Rolipram (3 μM) suppressed ROM generation without detectable increase in cAMP content. Incubation of glomeruli with forskolin, which increased cAMP content in glomeruli tenfold, inhibited ROM generation to a similar degree as rolipram. The suppression of ROM generation by rolipram was prevented by Rp-cAMPS, a specific inhibitor of protein kinase A (PKA) activity. Further, incubation of glomeruli with rolipram elicited marked in situ activation of PKA (+100%), as documented by increase in the (-cAMP/+cAMP) PKA activity ratio. We suggest that selective inhibitor of PDE-IV rolipram acted via the cAMP-signaling pathway and suppressed ROM generation possibly via phosphorylating ras-type GTP-binding protein component of NADPH oxidase and thereby blocking assembly of functional NADPH oxidase complex. Results also suggest that ROM burst in glomeruli is modulated by a distinct cAMP-signaling pathway which is controlled by PDE-IV. We surmise that inhibitors of PDE-IV might be effective agents for suppression of ROM generation in glomeruli in vivo and attenuation of glomerular injury.

AB - Several independent studies indicate that synthetic inhibitors of cyclic-3',5'-nucleotide phosphodiesterase (PDE) isozymes, especially inhibitors of PDE-IV, are potent agents which suppress generation of reactive oxygen metabolites (ROM) by NADPH oxidase in leukocytes. Recent studies also show that NADPH oxidase is present in all cell types populating glomeruli. In view of this, we investigated PDE isozymes and their relation to ROM in isolated rat glomeruli. Glomeruli have the capacity to hydrolyze cAMP by isozymes PDE-II, PDE-III and PDE-IV, whereas cGMP is hydrolyzed by PDE-I and PDE-V. Inhibitor of PDE-IV rolipram inhibited significantly (cca 40 to 50%) ROM generation in response to stimulation by phorbol myristate acetate (PMA). Inhibitor of PDE-III cilostamide had only minor suppressive effects and inhibitors of other PDE isozymes did not influence ROM generation. Rolipram (3 μM) suppressed ROM generation without detectable increase in cAMP content. Incubation of glomeruli with forskolin, which increased cAMP content in glomeruli tenfold, inhibited ROM generation to a similar degree as rolipram. The suppression of ROM generation by rolipram was prevented by Rp-cAMPS, a specific inhibitor of protein kinase A (PKA) activity. Further, incubation of glomeruli with rolipram elicited marked in situ activation of PKA (+100%), as documented by increase in the (-cAMP/+cAMP) PKA activity ratio. We suggest that selective inhibitor of PDE-IV rolipram acted via the cAMP-signaling pathway and suppressed ROM generation possibly via phosphorylating ras-type GTP-binding protein component of NADPH oxidase and thereby blocking assembly of functional NADPH oxidase complex. Results also suggest that ROM burst in glomeruli is modulated by a distinct cAMP-signaling pathway which is controlled by PDE-IV. We surmise that inhibitors of PDE-IV might be effective agents for suppression of ROM generation in glomeruli in vivo and attenuation of glomerular injury.

UR - http://www.scopus.com/inward/record.url?scp=0028244071&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028244071&partnerID=8YFLogxK

M3 - Article

VL - 46

SP - 28

EP - 36

JO - Kidney International

JF - Kidney International

SN - 0085-2538

IS - 1

ER -