Direct in vivo inhibition of the nuclear cell cycle cascade in experimental mesangial proliferative glomerulonephritis with Roscovitine, a novel cyclin-dependent kinase antagonist.

Abstract

Glomerular injury is characterized by mesangial cell (MC) proliferation and matrix formation. We sought to determine if reducing the activity of cyclin-dependent kinase 2 (CDK2) with the purine analogue, Roscovitine, decreased MC proliferation in vitro and in vivo. Roscovitine (25 microM) inhibited FCS-induced proliferation (P < 0.0001) in cultured MC. Rats with experimental mesangial proliferative glomerulonephritis (Thy1 model) were divided into two groups. A prevention group received daily intraperitoneal injections of Roscovitine in DMSO (2.8 mg/kg) starting at day 1. A treatment group received daily Roscovitine starting at day 3, when MC proliferation was established. Control Thy1 rats received DMSO alone. MC proliferation (PCNA +/OX7 + double immunostaining) was reduced by > 50% at days 5 and 10 in the Roscovitine prevention group, and at day 5 in the treatment group (P < 0.0001). Early administration of Roscovitine reduced immunostaining for collagen type IV, laminin, and fibronectin at days 5 and 10 (r = 0.984; P < 0.001), which was associated with improved renal function (urinary protein/creatinine, blood urea nitrogen, P < 0.05). We conclude that reducing the activity of CDK2 with Roscovitine in experimental glomerulonephritis decreases cell proliferation and matrix production, resulting in improved renal function, and may be a useful therapeutic intervention in disease characterized by proliferation.

• Authors: J W Pippin, Q Qu, L Meijer, S J Shankland
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 100 Issue 10 Pg. 2512-20 (Nov 15 1997) ISSN: 0021-9738 [Print] United States
• PMID: 9366565 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Enzyme Inhibitors
• Fibronectins
• Laminin
• Purines
• Roscovitine
• Collagen
• Protein Kinases
• histone H1 kinase
• Protein Serine-Threonine Kinases
• CDC2-CDC28 Kinases
• Cdk2 protein, rat
• Cyclin-Dependent Kinase 2
• Cyclin-Dependent Kinases

Topics

• Animals
• CDC2-CDC28 Kinases
• Cell Cycle (drug effects, physiology)
• Cell Nucleus (drug effects, ultrastructure)
• Cells, Cultured
• Collagen (biosynthesis)
• Cyclin-Dependent Kinase 2
• Cyclin-Dependent Kinases (antagonists & inhibitors, physiology)
• Enzyme Inhibitors (pharmacology)
• Fibronectins (biosynthesis)
• Glomerular Mesangium (drug effects, pathology, physiopathology)
• Glomerulonephritis, Membranoproliferative (pathology, physiopathology)
• Kidney Function Tests
• Laminin (biosynthesis)
• Protein Kinases (metabolism)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, physiology)
• Purines (pharmacology)
• Rats
• Rats, Wistar
• Roscovitine