The cyclin kinase inhibitor p21WAF1, CIP1 is increased in experimental diabetic nephropathy: potential role in glomerular hypertrophy.
High glucose inhibits mesangial cell proliferation in vitro and induces hypertrophy in mesangial cells in culture and in experimental diabetic nephropathy. Cell growth is ultimately controlled at the level of the cell cycle by cell cycle regulatory proteins. Cell cycle progression requires that cyclin-dependent kinases be activated by cyclins. Cyclin kinase inhibitors (CKI) inactivate cyclin-dependent kinases, causing cell cycle arrest. In the current study, high glucose-induced mesangial cell hypertrophy in vitro is shown to be associated with increased levels of the CKI p21, but not p27. In the streptozotocin model of experimental diabetes in the mouse, glomerular hypertrophy was associated with a selective increase in p21 expression, whereas the levels of the CKI p27 and p57 did not change. Unlike many other forms of glomerular injury, diabetic nephropathy was not associated with increased apoptosis. These results support a role for p21 in causing glomerular cell hypertrophy in diabetic nephropathy.
Kuan
C J
CJ
Division of Nephrology, University of Washington Medical Center, Seattle 98195, USA.
al-Douahji
M
M
Shankland
S J
SJ
D000818:Animals; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016213:Cyclins / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000378:metabolism*; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D005947:Glucose / Q000494:pharmacology; D006984:Hypertrophy; D007678:Kidney Glomerulus / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley
C493957:Cdkn1a protein, mouse; C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D018844:Cyclin-Dependent Kinases; D005947:Glucose