p35, the non-cyclin activator of Cdk5, protects podocytes against apoptosis in vitro and in vivo.
Cyclin-dependent kinase-5 is widely expressed and predominantly regulated by the non-cyclin activator p35. Since we recently showed that expression of p35 in the kidney is restricted to podocytes, we examined here its function in mice in which p35 was genetically deleted. The mice did not exhibit kidney abnormalities during glomerular development or during adult life. Conditionally immortalized cultured podocytes, derived from these null mice, did not have any change in their morphology, differentiation, or proliferation. However, when these cultured podocytes were exposed to UV-C irradiation, serum depletion, puromycin aminonucleoside, or transforming growth factor-beta-1, they showed increased apoptosis compared to those from wild-type mice. Levels of Bcl-2 were decreased in these null podocytes but increased after transduction with human p35. Restoration of p35 or the ectopic expression of Bcl-2 reduced the susceptibility of p35-null podocytes to apoptosis. Experimental glomerulonephritis, characterized by podocyte apoptosis and subsequent crescent formation, was utilized to test these findings in vivo. Podocyte apoptosis was significantly increased in diseased p35-null compared with wild-type mice, accompanied by increased glomerulosclerosis and decreased renal function. Our study shows that p35 does not affect glomerulogenesis but controls podocyte survival following injury, in part, by regulating Bcl-2 expression.
Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington 98195-6521, USA.
Paul T
PT
Brinkkoetter
Jimmy S
JS
Wu
Takamoto
T
Ohse
Ronald D
RD
Krofft
Bernhard
B
Schermer
Thomas
T
Benzing
Jeffrey W
JW
Pippin
Stuart J
SJ
Shankland
D000818:Animals; D017209:Apoptosis / Q000276:immunology / Q000502:physiology*; D002454:Cell Differentiation / Q000276:immunology / Q000502:physiology; D051360:Cyclin-Dependent Kinase 5 / Q000276:immunology / Q000378:metabolism*; D016213:Cyclins / Q000276:immunology / Q000378:metabolism*; D005921:Glomerulonephritis / Q000276:immunology / Q000378:metabolism; D007668:Kidney / Q000276:immunology / Q000378:metabolism*; D007674:Kidney Diseases / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D050199:Podocytes / Q000276:immunology / Q000378:metabolism*; D018809:Proliferating Cell Nuclear Antigen / Q000276:immunology / Q000378:metabolism; D011692:Puromycin Aminonucleoside / Q000276:immunology / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000276:immunology / Q000378:metabolism
D016213:Cyclins; D018809:Proliferating Cell Nuclear Antigen; D053773:Transforming Growth Factor beta1; D011692:Puromycin Aminonucleoside; D051360:Cyclin-Dependent Kinase 5