title: Treatment with a cyclin-dependent kinase inhibitor, seliciclib, is effective in reducing glomerular macrophage numbers and the severity of established experimental glomerulonephritis.
abstract: OBJECTIVE
  The cyclin-dependent kinase inhibitor, seliciclib (R-roscovitine, CYC202), has anti-proliferative activity through its inhibition of cyclin-dependent kinase 2. We hypothesized that treatment with seliciclib would reduce glomerular macrophage numbers and glomerular crescent formation in experimental crescentic glomerulonephritis even when treatment is started after onset of disease.
  
  
  METHODS
  Nephrotoxic nephritis (NTN) was induced in Wistar Kyoto rats. In experiment 1, seliciclib (150 mg/kg per day) was given by oral gavage from 1 h before induction of NTN and continued to day 14. In experiment 2, treatment was started on day 4 of NTN and continued to day 14 in order to examine the effect of seliciclib in established glomerulonephritis.
  
  
  RESULTS
  In experiment 1, seliciclib reduced proteinuria (119.5 ± 13.9 vs 191.4 ± 18.8 mg/day, P < 0.01), serum creatinine (54.0 ± 3.0 vs 81.0 ± 2.5 µmol/L, P < 0.005) and glomerular crescent score (23.9 ± 2.1 vs 44.6 ± 2.2, P < 0.005) in comparison with controls. In experiment 2, seliciclib ameliorated established glomerulonephritis, with reduction in proteinuria (58 ± 16 vs 165 ± 13 mg/day, P < 0.005), serum creatinine (39 ± 3 vs 62 ± 5 µmol/L, P < 0.05), glomerular macrophage numbers (6.8 ± 2.5 vs 18.5 ± 1.2 ED1+ cells per glomerular cross section, P < 0.05), glomerular cell proliferation (1.2 ± 0.37 vs 4.2 ± 0.80 bromodeoxyuridine (BrdU)+ cells per glomerular section, P < 0.05) and crescent score (10.8 ± 1.6 vs 43.9 ± 1.4, P < 0.05), in comparison with the controls.
  
  
  CONCLUSIONS
  Seliciclib is effective in both prevention and treatment of established crescentic glomerulonephritis in Wistar Kyoto rats, in association with a reduction in the number of glomerular macrophages. We suggest that seliciclib, or other cyclin-dependent kinase inhibitors, may represent a novel therapeutic approach for patients with proliferative glomerulonephritis.
authors.affiliation: Renal Section, Department of Medicine, Imperial College Kidney and Transplant Institute, Imperial College London, London, UK.
authors.forename: Abdulmunem M
authors.initials: AM
authors.lastname: Sheryanna
authors.forename: Jennifer
authors.initials: J
authors.lastname: Smith
authors.forename: Gurjeet
authors.initials: G
authors.lastname: Bhangal
authors.forename: Anna
authors.initials: A
authors.lastname: Barnett
authors.forename: Steven
authors.initials: S
authors.lastname: McClue
authors.forename: Frederick W K
authors.initials: FW
authors.lastname: Tam
authors.forename: Terence
authors.initials: T
authors.lastname: Cook
authors.forename: Charles D
authors.initials: CD
authors.lastname: Pusey
mesh_terms: D000284:Administration, Oral; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects* / Q000473:pathology; D008297:Male; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011507:Proteinuria / Q000188:drug therapy / Q000201:enzymology; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011921:Rats, Inbred WKY; D000077546:Roscovitine; D012720:Severity of Illness Index; D013997:Time Factors
chemical_list: D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine; D003404:Creatinine; D018844:Cyclin-Dependent Kinases