Cyclin I protects podocytes from apoptosis.
The limited regenerative capacity of the glomerular podocyte following injury underlies the development of glomerulosclerosis and progressive renal failure in a diverse range of kidney diseases. We discovered that, in the kidney, cyclin I is uniquely expressed in the glomerular podocyte, and have constructed cyclin I knock-out mice to explore the biological function of cyclin I in these cells. Cyclin I knock-out (-/-) podocytes showed an increased susceptibility to apoptosis both in vitro and in vivo. Following induction of experimental glomerulonephritis, podocyte apoptosis was increased 4-fold in the cyclin I -/- mice, which was associated with dramatically decreased renal function. Our previous data showed that the Cdk inhibitor p21(Cip1/Waf1) protects podocytes from certain apoptotic stimuli. In cultured cyclin I -/- podocytes, the level of p21(Cip1/Waf1) was lower at base line, had a shorter half-life, and declined more rapidly in response to apoptotic stimuli than in wild-type cells. Enforced expression of p21(Cip1/Waf1) reversed the susceptibility of cyclin I -/- podocytes to apoptosis. Cyclin I protects podocytes from apoptosis, and we provide preliminary data to suggest that this is mediated by stabilization of p21(Cip1/Waf1).
Griffin
Siân V
SV
Department of Medicine, Division of Nephrology, University of Washington School of Medicine, Seattle, 98195, USA.
Olivier
J Paul
JP
Pippin
Jeffrey W
JW
Roberts
James M
JM
Shankland
Stuart J
SJ
D000818:Animals; D017209:Apoptosis; D056749:Cyclin I; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology; D016213:Cyclins / Q000502:physiology*; D005921:Glomerulonephritis / Q000473:pathology / Q000503:physiopathology; D007668:Kidney / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D050199:Podocytes / Q000166:cytology*
C534757:Ccni protein, mouse; C493957:Cdkn1a protein, mouse; D056749:Cyclin I; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins