Stimulation of soluble guanylyl cyclase inhibits mesangial cell proliferation and matrix accumulation in experimental glomerulonephritis.
To date, no specific treatment is established in mesangial proliferative glomerulonephritis in humans. Specific stimulation of soluble guanylyl cyclase (sGC), an enzyme catalyzing the synthesis of cGMP from GTP, can be achieved by the novel pyrazolopyridine derivative BAY 41-2272. The effect of sGC stimulation via BAY 41-2272 on mesangial proliferation was assessed in vivo using a mesangial proliferative glomerulonephritis model in rats (anti-Thy1 model). Renal biopsies, as well as glomerular isolates, urine samples, and blood samples were compared in BAY 41-2272- and placebo-treated groups during anti-Thy1 nephritis. The sGC beta(1)-subunit is upregulated during anti-Thy1 nephritis and mainly confined to mesangial areas by immunohistochemistry. Specific therapeutic sGC stimulation during anti-Thy1 nephritis in vivo was achieved via BAY 41-2272 treatment as demonstrated by increased glomerular cGMP levels causing inhibition of mesangial proliferation, glomerular matrix accumulation, and proteinuria compared with placebo-treated animals. sGC is tightly regulated in glomeruli during experimental glomerulonephritis. Considering its beneficial antiproliferative, antifibrotic, and antiproteinuric effect in experimental glomerulonephritis, the therapeutic stimulation of sGC could become a promising future goal in mesangial proliferative glomerulonephritis in humans.
Hohenstein
Bernd
B
Div. of Nephrology, Univ. Erlangen-Nuremberg, Loschgestrasse 8, 91054 Erlangen, Germany.
Daniel
Christoph
C
Wagner
Andrea
A
Stasch
Johannes-Peter
JP
Hugo
Christian
C
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D002455:Cell Division / Q000502:physiology; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005920:Glomerular Mesangium / Q000201:enzymology* / Q000276:immunology / Q000473:pathology*; D005921:Glomerulonephritis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D006162:Guanylate Cyclase; D007518:Isoantibodies; D008264:Macrophages / Q000473:pathology; D009000:Monocytes / Q000473:pathology; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase; D015854:Up-Regulation / Q000502:physiology
C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D000959:Antihypertensive Agents; D007518:Isoantibodies; D011720:Pyrazoles; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; C035678:anti-Thy antibody; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase