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1 Department of Nephrology and Center of Cardiovascular Research, Charite University Medicine, Berlin, Germany
2 Department Cell Biology and Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
* To whom correspondence should be addressed. E-mail: Harm.Peters{at}charite.de.
Cyclic GMP serves
as the main second messenger of nitric oxide (NO). Antifibrotic effects of enhancing renal cGMP
levels have recently been documented in experimental acute anti-thy1 glomerulonephritis. The
present study compares the effects of the cGMP production-increasing soluble guanylate cyclase
(sGC) stimulator Bay 41-2272 and cGMP degradation-limiting phosphodiesterase inhibitor
pentoxifylline (PTX) in a progressive model of renal fibrosis. One week after induction of anti-thy1-
induced chronic glomerulosclerosis (cGS), rats were randomly assigned to cGS, cGS+Bay
41-2272 (10 mg/kg body weight/d) or cGS+PTX (50 mg/kg body weight/d). Both interventions
reduced systolic blood pressure significantly. In week 16, tubulointerstitial expressions of soluble
guanylate cyclase mRNA and NO-induced cGMP synthesis were increased in untreated cGS
animals, while its glomerular activity was depressed when compared to normal controls.
Tubulointerstitial and glomerular cGMP production in response to NO were significantly enhanced
in the Bay 41-2272-treated animals, but not in the PTX group. Bay 41-2272 administration
resulted in marked reductions of glomerular and tubulointerstitial histological matrix
accumulation, expression of TGF-
1 and fibronectin, macrophage infiltration and cell
proliferation as well as improved renal function. In contrast, only moderate and non-significant
renoprotective changes were observed in the cGS+PTX group. In conclusion, increasing renal
cGMP production through Bay 41-2272 both significantly improved renal NO-cGMP signaling and
limited progression in anti-thy1-induced chronic renal fibrosis, while inhibition of cGMP
degradation by PTX was only moderately effective. The findings indicate that pharmacological
enhancement of renal cGMP levels by soluble guanylate cyclase stimulation represents a novel
and effective anti-fibrotic approach in progressive kidney disorders.
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