title: Enhancing cGMP in experimental progressive renal fibrosis: soluble guanylate cyclase stimulation vs. phosphodiesterase inhibition.
abstract: cGMP 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-Thy-1 glomerulonephritis. The present study compares the effects of the cGMP production-increasing soluble guanylate cyclase (sGC) stimulator BAY 41-2272 with those of the cGMP degradation-limiting phosphodiesterase inhibitor pentoxifylline (PTX) in a progressive model of renal fibrosis. At 1 wk after induction of anti-Thy-1-induced chronic glomerulosclerosis (cGS), rats were randomly assigned to groups as follows: cGS, cGS + BAY 41-2272 (10 mg x kg body wt(-1) x day(-1)), or cGS + PTX (50 mg x kg body wt(-1) x day(-1)). BAY 41-2272 and PTX reduced systolic blood pressure significantly. At 16 wk, tubulointerstitial expressions of sGC mRNA and NO-induced cGMP synthesis were increased in untreated cGS animals, whereas their glomerular activity was depressed compared with normal controls. Tubulointerstitial and glomerular cGMP production in response to NO were significantly enhanced in animals treated with BAY 41-2272, but not in those treated with PTX. BAY 41-2272 administration resulted in marked reductions of glomerular and tubulointerstitial histological matrix accumulation, expression of TGF-beta1 and fibronectin, macrophage infiltration, and cell proliferation as well as improved renal function. In contrast, only moderate and nonsignificant renoprotective changes were observed in the cGS + PTX group. In conclusion, increasing renal cGMP production through BAY 41-2272 significantly improved renal NO-cGMP signaling and limited progression in anti-Thy-1-induced chronic renal fibrosis, whereas inhibition of cGMP degradation by PTX was only moderately effective. The findings indicate that pharmacological enhancement of renal cGMP levels by sGC stimulation represents a novel and effective antifibrotic approach in progressive kidney disorders.
authors.affiliation: Dept. of Nephrology, Charité, Campus Mitte, Humboldt Univ., Schumannstrasse 20/21, D-10098 Berlin, Germany.
authors.forename: Yingrui
authors.initials: Y
authors.lastname: Wang
authors.forename: Stephanie
authors.initials: S
authors.lastname: Krämer
authors.forename: Tanja
authors.initials: T
authors.lastname: Loof
authors.forename: Sebastian
authors.initials: S
authors.lastname: Martini
authors.forename: Susanne
authors.initials: S
authors.lastname: Kron
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawachi
authors.forename: Fuijo
authors.initials: F
authors.lastname: Shimizu
authors.forename: Hans-H
authors.initials: HH
authors.lastname: Neumayer
authors.forename: Harm
authors.initials: H
authors.lastname: Peters
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism*; D004326:Drinking / Q000187:drug effects; D005355:Fibrosis / Q000201:enzymology*; D005921:Glomerulonephritis / Q000201:enzymology*; D006162:Guanylate Cyclase / Q000378:metabolism / Q000494:pharmacology*; D007668:Kidney / Q000201:enzymology* / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D010431:Pentoxifylline / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000502:physiology*; D011507:Proteinuria / Q000188:drug therapy / Q000276:immunology; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
chemical_list: C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D009569:Nitric Oxide; D010727:Phosphoric Diester Hydrolases; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D010431:Pentoxifylline