TY - JOUR
T1 - The cyclin kinase inhibitor p21(CIP1/WAF1) limits glomerular epithelial cell proliferation in experimental glomerulonephritis
AU - Yoon-Goo, Kim
AU - Alpers, Charles E.
AU - Brugarolas, James
AU - Johnson, Richard J.
AU - Couser, William G.
AU - Shankland, Stuart J.
N1 - Funding Information:
This work was supported by National Institutes of Health grants (DK 52121, DK51096, DK34198) and a George M. O’Brien Kidney Reseach Center Award (DK47659). Y.-G.K. was supported by Samsung Medical Center, Sungkyunkwan University, Seoul, Korea.
PY - 1999
Y1 - 1999
N2 - Background. During glomerulogenesis, visceral glomerular epithelial cells (VECs) exit the cell cycle and become terminally differentiated and quiescent. In contrast to other resident glomerular cells, VECs undergo little if any proliferation in response to injury. However, the mechanisms for this remain unclear. Cell proliferation is controlled by cell-cycle regulatory proteins where the cyclin-dependent kinase inhibitor p21(Cip1,WAF1) (p21) inhibits cell proliferation and is required for differentiation of many nonrenal cell types. Methods. To test the hypothesis that p21 is required to maintain a differentiated and quiescent VEC phenotype, experimental glomerulonephritis was induced in p21 knockout (-/-) and p21 wild-type (+/+) mice with antiglomerular antibody. DNA synthesis (proliferating cell nuclear antigen, bromodeoxyuridine staining), VEC proliferation (multilayers of cells in Bowman's space), matrix accumulation (periodic acid-Schiff, silver staining), apoptosis (TUNEL), and renal function (serum urea nitrogen) were studied on days 5 and 14 (N = 6 per time point). VECs were identified by location, morphology, ezrin staining, and electron microscopy. VEC differentiation was measured by staining for Wilms' tumor-1 gene. Results. Kidneys from unmanipulated p21-/- mice were histologically normal and did not have increased DNA synthesis, suggesting that p21 was not required for the induction of VEC terminal differentiation. Proliferating cell nuclear antigen and bromodeoxyuridine staining was increased 4.3- and 3.3-fold, respectively, in p21-/- mice with glomerulonephritis (P < 0.0001 vs. p21+/+ mice). At each time point, VEC proliferation was also increased in nephritic p21-/- mice (P < 0.0001 vs. p21+/+ mice). VEC re-entry into the cell cycle was associated with the loss of Wilms' tumor-1 gene staining. Nephritic p21-/- mice had increased extracellular matrix protein accumulation and apoptosis and decreased renal function (serum urea nitrogen) compared with p21+/+ mice (P < 0.001). Conclusion. These results show that the cyclin kinase inhibitor p21 is not required by VECs to attain a terminally differentiated VEC phenotype. However, the loss of p21, in disease states, is associated with VEC re-entry into the cell cycle and the development of a dedifferentiated proliferative phenotype.
AB - Background. During glomerulogenesis, visceral glomerular epithelial cells (VECs) exit the cell cycle and become terminally differentiated and quiescent. In contrast to other resident glomerular cells, VECs undergo little if any proliferation in response to injury. However, the mechanisms for this remain unclear. Cell proliferation is controlled by cell-cycle regulatory proteins where the cyclin-dependent kinase inhibitor p21(Cip1,WAF1) (p21) inhibits cell proliferation and is required for differentiation of many nonrenal cell types. Methods. To test the hypothesis that p21 is required to maintain a differentiated and quiescent VEC phenotype, experimental glomerulonephritis was induced in p21 knockout (-/-) and p21 wild-type (+/+) mice with antiglomerular antibody. DNA synthesis (proliferating cell nuclear antigen, bromodeoxyuridine staining), VEC proliferation (multilayers of cells in Bowman's space), matrix accumulation (periodic acid-Schiff, silver staining), apoptosis (TUNEL), and renal function (serum urea nitrogen) were studied on days 5 and 14 (N = 6 per time point). VECs were identified by location, morphology, ezrin staining, and electron microscopy. VEC differentiation was measured by staining for Wilms' tumor-1 gene. Results. Kidneys from unmanipulated p21-/- mice were histologically normal and did not have increased DNA synthesis, suggesting that p21 was not required for the induction of VEC terminal differentiation. Proliferating cell nuclear antigen and bromodeoxyuridine staining was increased 4.3- and 3.3-fold, respectively, in p21-/- mice with glomerulonephritis (P < 0.0001 vs. p21+/+ mice). At each time point, VEC proliferation was also increased in nephritic p21-/- mice (P < 0.0001 vs. p21+/+ mice). VEC re-entry into the cell cycle was associated with the loss of Wilms' tumor-1 gene staining. Nephritic p21-/- mice had increased extracellular matrix protein accumulation and apoptosis and decreased renal function (serum urea nitrogen) compared with p21+/+ mice (P < 0.001). Conclusion. These results show that the cyclin kinase inhibitor p21 is not required by VECs to attain a terminally differentiated VEC phenotype. However, the loss of p21, in disease states, is associated with VEC re-entry into the cell cycle and the development of a dedifferentiated proliferative phenotype.
KW - Cell cycle
KW - Cyclin dependent kinase
KW - Glomerulus
KW - Injury
KW - Kidney
KW - Podocyte
KW - Visceral glomerular epithelial cells
KW - p21
UR - http://www.scopus.com/inward/record.url?scp=0033033630&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033033630&partnerID=8YFLogxK
U2 - 10.1046/j.1523-1755.1999.00504.x
DO - 10.1046/j.1523-1755.1999.00504.x
M3 - Article
C2 - 10354282
AN - SCOPUS:0033033630
SN - 0085-2538
VL - 55
SP - 2349
EP - 2361
JO - Kidney international
JF - Kidney international
IS - 6
ER -