Limitation of podocyte proliferation improves renal function in experimental crescentic glomerulonephritis.
BACKGROUND
Many forms of glomerular diseases are characterized by injury to the glomerular visceral epithelial cell, or podocyte, which usually results in depletion of podocyte number. However, in diseases where podocyte proliferation occurs there is a rapid decline in renal function. The consequences of inhibiting podocyte proliferation on renal function have not been fully established. At the level of the cell cycle, cyclin-dependent kinase 2 (CDK2) is required for proliferation.


METHODS
To determine if decreasing podocyte proliferation improves renal function, CDK2 activity was reduced with the purine analogue roscovitine in mice with antibody-induced experimental glomerulonephritis. Nephritic animals given vehicle, dimethyl sulfoxide (DMSO), served as control. Blood urea nitrogen (BUN), proteinuria, and renal histology were assessed at days 5 and 14 of disease.


RESULTS
Inhibiting CDK2 activity resulted in a marked decrease in glomerular DNA synthesis [5-bromo-2'-deoxyridine (BrdU) staining] in Roscovitine-treated animals at day 5 of nephritis (P < 0.05 versus control). This was associated with a significant decrease in BUN and glomerulosclerosis at day 14 (P < 0.01 versus control) and a decrease in the accumulation of the extracellular matrix protein laminin (P < 0.01 versus control).


CONCLUSIONS
Inhibiting podocyte proliferation in experimental glomerulonephritis is associated with improvement in renal function and histology, suggesting that inhibiting CDK2 activity is a potential therapeutic target for glomerular diseases characterized by podocyte proliferation.
Griffin
Siân V
SV
Division of Nephrology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington 98195, USA. svgriff@u.washington.edu
Krofft
Ronald D
RD
Pippin
Jeffrey W
JW
Shankland
Stuart J
SJ
D000818:Animals; D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D049109:Cell Proliferation; D051357:Cyclin-Dependent Kinase 2; D004247:DNA / Q000096:biosynthesis; D004847:Epithelial Cells / Q000166:cytology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005921:Glomerulonephritis / Q000473:pathology* / Q000503:physiopathology; D007668:Kidney / Q000503:physiopathology*; D007678:Kidney Glomerulus / Q000166:cytology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011687:Purines / Q000494:pharmacology; D000077546:Roscovitine
D016326:Extracellular Matrix Proteins; D011687:Purines; D000077546:Roscovitine; D004247:DNA; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2