Stimulation of soluble guanylate cyclase slows progression in anti-thy1-induced chronic glomerulosclerosis.
BACKGROUND
A critical role of soluble guanylate cyclase and nitric oxide-dependent cyclic 3',5'-guanosine monophosphate (cGMP) production for glomerular matrix expansion has recently been documented in a rat model of acute anti-thy1 glomerulonephritis. The present study analyzes the renal activity of the nitric oxide-cGMP signaling cascade in and the effect of the specific soluble guanylate cyclase stimulator Bay 41-2272 on a progressive model of anti-thy1-induced chronic glomerulosclerosis.


METHODS
Anti-thy1 glomerulosclerosis was induced by injection of anti-thy1 antibody into uninephrectomized rats. One week after disease induction, animals were randomly assigned to chronic glomerulosclerosis, chronic glomerulosclerosis plus Bay 41-2272 (10 mg/kg body weight/day) or chronic glomerulosclerosis plus hydralazine (15 mg/kg body weight/day). In week 16, analysis included effects on systolic blood pressure, proteinuria, kidney function, glomerular and tubulointerstitial matrix protein accumulation, expression of transforming growth factor-beta1 (TGF-beta1), fibronectin and plasminogen activator inhibitor type 1 (PAI-1), macrophage infiltration, cell proliferation, basal and nitric oxide-stimulated cGMP production as well as tubulointerstitial mRNA expression of alpha 1 and beta 1 soluble guanylate cyclase.


RESULTS
The moderately elevated systolic blood pressure seen in the chronic glomerulosclerosis group was comparably decreased by both treatments. Compared to normal controls, soluble guanylate cyclase mRNA expression and nitric oxide-stimulated cGMP production were up-regulated in the tubulointerstitium of the untreated chronic glomerulosclerosis animals, while its activity was decreased in glomeruli. Bay 41-2272 treatment enhanced glomerular and tubulointerstitial nitric oxide-cGMP signaling significantly. This went along with markedly reduced glomerular and tubulointerstitial macrophage infiltration, number of proliferating cells, matrix expression and accumulation, as well as improved kidney function. In contrast, hydralazine therapy did not significantly affect renal nitric oxide-cGMP signaling, macrophage number, cell proliferation, matrix protein expression and accumulation.


CONCLUSIONS
Glomerular and tubulointerstitial soluble guanylate cyclase activity are discordantly altered in anti-thy1-induced chronic glomerulosclerosis. Stimulation of soluble guanylate cyclase signaling by Bay 41-2272 limits the progressive course of this model toward tubulointerstitial fibrosis and impaired renal function at least in part in a blood pressure-independent manner. The results suggest that soluble guanylate cyclase activation counteracts fibrosis and progression in chronic renal disease.
Wang
Yingrui
Y
Department of Nephrology and Center of Cardiovascular Research, Charité University Medicine Berlin, Charité Campus Mitte, Humboldt University, Berlin, Germany.
Krämer
Stephanie
S
Loof
Tanja
T
Martini
Sebastian
S
Kron
Susanne
S
Kawachi
Hiroshi
H
Shimizu
Fuijo
F
Neumayer
Hans-H
HH
Peters
Harm
H
D000818:Animals; D015415:Biomarkers; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight; D002908:Chronic Disease; D018450:Disease Progression; D004435:Eating; D004789:Enzyme Activation / Q000187:drug effects; D005355:Fibrosis; D015870:Gene Expression; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D006162:Guanylate Cyclase; D006830:Hydralazine / Q000494:pharmacology; D007518:Isoantibodies / Q000494:pharmacology*; D007678:Kidney Glomerulus / Q000201:enzymology / Q000473:pathology / Q000502:physiology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D011507:Proteinuria / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000071756:Soluble Guanylyl Cyclase; D014665:Vasodilator Agents / Q000494:pharmacology
C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D015415:Biomarkers; D007518:Isoantibodies; D011720:Pyrazoles; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D014665:Vasodilator Agents; C035678:anti-Thy antibody; D006830:Hydralazine; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase