Dexamethasone-dependent modulation of cyclic GMP synthesis in podocytes.
Podocytes may be direct target for glucocorticoid therapy in glomerular proteinuric disease. Permeability of podocytes largely depends on their capacity to migrate which involves the contractile apparatus in their foot processes. In this study, we examined the effect of synthetic glucocorticoid dexamethasone (DEX) on the ability of podocytes to produce cyclic guanosine monophosphate (cGMP) in the presence of vasoactive factors, atrial natriuretic peptide (ANP), nitric oxide (NO), and angiotensin II (Ang II). We investigated also the effects of cGMP and DEX on podocyte motility. Primary rat podocytes and immortalized mouse podocytes were pretreated with 1 µM DEX for 4 or 24 h. Glomerular hypertension was mimicked by subjecting the cells to mechanical stress. Total and subcellular cGMP levels were determined in podocytes incubated with 0.1 µM ANP, 1 µM S-nitroso-N-acetyl penicillamine (SNAP), and 1 µM Ang II. Cell motility was estimated by a wound-healing assay. The ANP-dependent production of cGMP increased after 4 h exposition to DEX, but was attenuated after 24 h. Adversely, a 24-h pretreatment with DEX augmented the NO-dependent cGMP synthesis. Ang II suppressed the ANP-dependent cGMP production and the effect was enhanced by DEX in mechanical stress conditions. Mechanical stress reduced total cGMP production in the presence of all stimulators, whereas extracellular to total cGMP ratio increased. 8-Br cGMP enhanced podocyte migration which was accompanied by F-actin disassembly. In the presence of DEX these effects were prevented. We conclude that DEX modulates the production of cGMP in podocytes stimulated with vasoactive factors such as Ang II, ANP, and NO, and the effect is time-dependent. cGMP increases podocyte motility, which is prevented by DEX. This mechanism may account for the antiproteinuric effect of glucocorticoids.
Department of Pharmaceutical Pathophysiology, Medical University of Gdansk, Debinki 7, 80-211, Gdansk, Poland. blew@gumed.edu.pl.|Laboratory of Cellular and Molecular Nephrology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw/Gdansk, Poland. blew@gumed.edu.pl.
Barbara
B
Lewko
Department of Pharmaceutical Pathophysiology, Medical University of Gdansk, Debinki 7, 80-211, Gdansk, Poland. aniaw@gumed.edu.pl.
Anna
A
Waszkiewicz
Department of Pharmaceutical Pathophysiology, Medical University of Gdansk, Debinki 7, 80-211, Gdansk, Poland. anmar@gumed.edu.pl.
Anna
A
Maryn
Department of Immunopathology, Medical University of Gdansk, Gdansk, Poland. manata@wp.pl.
Magdalena
M
Gołos
Department of Pharmaceutical Pathophysiology, Medical University of Gdansk, Debinki 7, 80-211, Gdansk, Poland. ella@gumed.edu.pl.
Elżbieta
E
Latawiec
Department of Pathology and Experimental Rheumatology, Medical University of Gdansk, Gdansk, Poland. agnieszka.ela@gumed.edu.pl.
Agnieszka
A
Daca
Department of Pathophysiology, Medical University of Gdansk, Gdansk, Poland. jawit@gumed.edu.pl.
Jacek M
JM
Witkowski
Laboratory of Cellular and Molecular Nephrology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw/Gdansk, Poland. angielsk@gumed.edu.pl.
Stefan
S
Angielski
Laboratory of Cellular and Molecular Nephrology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw/Gdansk, Poland.
Jan
J
Stępiński
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000096:biosynthesis*; D003907:Dexamethasone / Q000494:pharmacology*; D005434:Flow Cytometry; D051379:Mice; D009569:Nitric Oxide / Q000494:pharmacology; D050199:Podocytes / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D017461:Receptors, Atrial Natriuretic Factor / Q000096:biosynthesis; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D013312:Stress, Physiological / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D000804:Angiotensin II; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D003907:Dexamethasone; D009320:Atrial Natriuretic Factor; D017461:Receptors, Atrial Natriuretic Factor; D006152:Cyclic GMP
Angiotensin II; Dexamethasone; Mechanical stress; Motility; Podocytes; cGMP