R-roscovitine (CYC202) alleviates renal cell proliferation in nephritis without aggravating podocyte injury.
BACKGROUND
Cyclin-dependent kinase (CDK) inhibition is a new therapeutic approach to proliferative glomerulonephritides. CDK2 is required for G(1)/S transition and DNA synthesis and is inhibited by CYC202 (R-roscovitine). Since podocytes express CDK2 in nephritis and since loss of podocytes contributes to glomerulosclerosis, the rationale of the present study was to test whether CDK2 inhibition is safe in instances of podocyte injury.


METHODS
Rats with passive Heymann nephritis, a model of membranous glomerulonephritis, were treated (day 3 to 30) with vehicle, low (25 mg/kg/day), or high (50 mg/kg/day) doses of CYC202.


RESULTS
On day 27, blood pressure was normal in nephritic controls and was dose-dependently reduced by CYC202. Urinary albumin excretion did not differ between the groups on days 9, 16, 23, and 30. To investigate podocyte injury, we assessed the glomerular de novo expression of desmin, which was markedly up-regulated in almost all passive Heymann nephritis glomeruli but was not significantly different between the three groups. No tubulointerstitial de novo expression of desmin or alpha-smooth muscle actin (alpha-SMA), or tubulointerstitial monocyte/macrophage infiltration was noted in any group. Biologic activity of CYC202 was evident in the form of a dose-dependent decrease in the number of glomerular and tubulointerstitial mitotic figures as compared to vehicle alone. Glomerular immunostaining for cyclin D1, a marker for G(0) to G(1) transition, was significantly decreased in CYC202 treated groups at day 9.


CONCLUSIONS
Whereas inhibition of CDKs by CYC202 reduced intrarenal cell proliferation in passive Heymann nephritis it did not aggravate podocyte damage, suggesting that this novel therapeutic approach is safe in renal diseases characterized by podocyte injury.
Milovanceva-Popovska
Maja
M
Division of Nephrology, University of Aachen, Aachen, Germany.
Kunter
Uta
U
Ostendorf
Tammo
T
Petermann
Arndt
A
Rong
Song
S
Eitner
Frank
F
Kerjaschki
Dontscho
D
Barnett
Anna
A
Floege
Jürgen
J
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005921:Glomerulonephritis / Q000473:pathology*; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology; D008297:Male; D011687:Purines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077546:Roscovitine; D019459:Urothelium / Q000187:drug effects / Q000473:pathology
D004791:Enzyme Inhibitors; D011687:Purines; D000077546:Roscovitine; D018844:Cyclin-Dependent Kinases