Dexamethasone-dependent modulation of cyclic GMP synthesis in podocytes

Abstract

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.

Quantitative deep mapping of the cultured podocyte proteome uncovers shifts in proteostatic mechanisms during differentiation

“…3, G and H). The impact of ANP signaling on podocytes is studied in vitro (38), but not in vivo, but the receptor is expressed also in vivo on mRNA level and protein level as shown by this and previous studies (29). ANP is elevated in congestive heart failure (9,12).…”

Cinaciguat ameliorates glomerular damage by reducing ERK1/2 activity and TGF-ß expression in type-1 diabetic rats

“…In our study, DM reduced both tubular and glomerular sGC immunoreactivity, which was attenuated by cinaciguat treatment. In the glomerulus, sGC plays an important role both in mesangial cells 56 and podocytes 57 . We suggest that the activation of oxidized sGC in podocytes and mesangial cells attenuated podocyte damage and restored nephrin and podocin expression by increasing intracellular cGMP levels in diabetic glomeruli, as shown by cGMP immunostaining.…”

Divergent effects of a designer natriuretic peptide CD-NP in the regulation of adipose tissue and metabolism

“…However, we did not see any changes in NPR-A mRNA levels with and without treatment on ND or HFD. Additionally, dexamethasone recently has been shown to upregulate NPR-C in podocytes [57] , whereas ANP previously has been shown to regulate cortisol release from adrenal glands of guinea pigs [58] . Hence, CD-NP might have an effect on glucocorticoid/cortisol levels in mice.…”