Changes in cell-cycle protein expression during experimental mesangial proliferative glomerulonephritis.
A characteristic response to mesangial cell injury is proliferation, which is closely linked to mesangial matrix accumulation and the progression of glomerular disease. Cell proliferation in non-renal cells in vitro is regulated at the level of the cell-cycle by specific cyclins and their catalytic partners, cyclin dependent kinases (CDK). Cyclin kinase inhibitors (CKI) prevent proliferation by inhibiting cell-cycle progression. However, the expression of cell-cycle regulatory proteins in the kidney and in renal disease is unknown. To determine this we studied the expression of cell-cycle proteins in vivo in normal rats and rats with experimental mesangial proliferative glomerulonephritis (Thy1 model). Normal quiescent rat glomeruli have a differential expression for CKI's, where p27Kip1 is highly expressed, and the levels for p21 (Cip1, Waf1, Sdi1, Cap20) (p21) are low. The onset of mesangial cell proliferation in Thy1 glomerulonephritis is associated with a reduction in p27Kip1 levels when mesangial cell proliferation is maximal. Mesangial cell proliferation in vivo is also associated with an increase in glomerular expression of cyclin A, and an increase in expression and activity for CDK2. The resolution of mesangial cell proliferation was associated with a return to baseline levels for p27Kip1, while the expression for p21 increased substantially. Furthermore, mesangial cell p21 expression was maintained following the resolution of proliferation. These results provide evidence for a complex interplay of cell-cycle regulatory proteins during the glomerular response to injury in vivo. The marked increase in CDK2 expression during mesangial cell proliferation and the sustained increase in p21 expression following the resolution of mesangial cell proliferation suggests that the in vivo expression of certain cell-cycle proteins may differ from that described in non-renal cells in vitro.
Shankland
S J
SJ
Division of Nephrology, University of Washington, Seattle, USA.
Hugo
C
C
Coats
S R
SR
Nangaku
M
M
Pichler
R H
RH
Gordon
K L
KL
Pippin
J
J
Roberts
J M
JM
Couser
W G
WG
Johnson
R J
RJ
D000818:Animals; D001706:Biopsy; D015153:Blotting, Western; D042846:CDC2-CDC28 Kinases; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D005920:Glomerular Mesangium / Q000737:chemistry* / Q000166:cytology / Q000473:pathology; D005921:Glomerulonephritis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D007518:Isoantibodies / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000737:chemistry / Q000473:pathology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D025521:Tumor Suppressor Proteins
C493958:Cdkn1a protein, rat; C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D007518:Isoantibodies; D008869:Microtubule-Associated Proteins; D025521:Tumor Suppressor Proteins; C035678:anti-Thy antibody; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases