The cyclin-dependent kinase inhibitor p21 limits murine mesangial proliferative glomerulonephritis

Toshiaki Monkawa, Jeffrey Pippin, Yoshikage Yo, Jeffrey B. Kopp, Charles E. Alpers, Stuart J. Shankland

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Background: Mesangial cell (MC) proliferation underlies increased matrix accumulation in glomerulonephritis (GN), and the resolution of MC proliferation occurs largely through apoptosis. Proliferation and apoptosis are controlled by specific cell cycle proteins, where cyclin-dependent kinase (CDK) inhibitors such as p21 bind target cyclin-CDK complexes. However, the role of p21 in acute mesangial proliferative GN is not known. This study was conducted to test the hypothesis that p21 regulates MC proliferation and apoptosis in anti-MC serum-induced GN. Methods: Age and sex matched wild-type (p21+/+) and p21-deficient (p21-/-) mice were injected with sheep anti-MC serum. Renal function (BUN, urinary albumin excretion), histology, DNA synthesis (BrdU. Ki-67) and apoptosis (TUNEL) were quantified at day 6 and day 12 (n = 6-8/time point). Results: In p21+/+ mice, anti-MC-serum induced mild MC proliferative GN, and glomerular p21 expression was increased. Renal function was worse in nephric p21-/- mice. PAS and silver staining revealed that p21-/- mice had typical features of MC proliferative GN with focal segmental tuft necrosis, focal mesangiolysis and focal mesangial hypercellularity. Occasional features of podocyte injury (swelling, vacuolization) were noted. Double immunostaining confirmed increased mesangial cell DNA synthesis in nephritic p21-/- mice at day 6. In contrast, there was no difference in glomerular apoptosis in nephritic p21+/+ and p21-/-mice at each time point. Glomerular lesions were accompanied by severe glomerular and tubulointerstitial fibrosis in p21-/- mice. Conclusions: This data shows that the CDK-inhibitor p21 regulates the MC proliferative response to immune-mediated injury. In contrast, p21 does not alter the apoptotic response, resulting in a delayed resolution in nephritic p21-/-mice.

Original languageEnglish
JournalNephron - Experimental Nephrology
Volume102
Issue number1
DOIs
Publication statusPublished - 2006 Jan

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Cyclin-Dependent Kinase Inhibitor p21
Mesangial Cells
Glomerulonephritis
Kidney
Apoptosis
Cyclin-Dependent Kinases
Cell Proliferation
Serum
Podocytes
Cell Cycle Proteins
Silver Staining
Cyclins
Blood Urea Nitrogen
DNA
In Situ Nick-End Labeling
Wounds and Injuries
Bromodeoxyuridine
Albumins
Sheep
Histology

Keywords

  • Cell cycle
  • Cyclin kinase inhibitor
  • Glomerulonephritis
  • p21

ASJC Scopus subject areas

  • Nephrology

Cite this

The cyclin-dependent kinase inhibitor p21 limits murine mesangial proliferative glomerulonephritis. / Monkawa, Toshiaki; Pippin, Jeffrey; Yo, Yoshikage; Kopp, Jeffrey B.; Alpers, Charles E.; Shankland, Stuart J.

In: Nephron - Experimental Nephrology, Vol. 102, No. 1, 01.2006.

Research output: Contribution to journalArticle

Monkawa, Toshiaki ; Pippin, Jeffrey ; Yo, Yoshikage ; Kopp, Jeffrey B. ; Alpers, Charles E. ; Shankland, Stuart J. / The cyclin-dependent kinase inhibitor p21 limits murine mesangial proliferative glomerulonephritis. In: Nephron - Experimental Nephrology. 2006 ; Vol. 102, No. 1.
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abstract = "Background: Mesangial cell (MC) proliferation underlies increased matrix accumulation in glomerulonephritis (GN), and the resolution of MC proliferation occurs largely through apoptosis. Proliferation and apoptosis are controlled by specific cell cycle proteins, where cyclin-dependent kinase (CDK) inhibitors such as p21 bind target cyclin-CDK complexes. However, the role of p21 in acute mesangial proliferative GN is not known. This study was conducted to test the hypothesis that p21 regulates MC proliferation and apoptosis in anti-MC serum-induced GN. Methods: Age and sex matched wild-type (p21+/+) and p21-deficient (p21-/-) mice were injected with sheep anti-MC serum. Renal function (BUN, urinary albumin excretion), histology, DNA synthesis (BrdU. Ki-67) and apoptosis (TUNEL) were quantified at day 6 and day 12 (n = 6-8/time point). Results: In p21+/+ mice, anti-MC-serum induced mild MC proliferative GN, and glomerular p21 expression was increased. Renal function was worse in nephric p21-/- mice. PAS and silver staining revealed that p21-/- mice had typical features of MC proliferative GN with focal segmental tuft necrosis, focal mesangiolysis and focal mesangial hypercellularity. Occasional features of podocyte injury (swelling, vacuolization) were noted. Double immunostaining confirmed increased mesangial cell DNA synthesis in nephritic p21-/- mice at day 6. In contrast, there was no difference in glomerular apoptosis in nephritic p21+/+ and p21-/-mice at each time point. Glomerular lesions were accompanied by severe glomerular and tubulointerstitial fibrosis in p21-/- mice. Conclusions: This data shows that the CDK-inhibitor p21 regulates the MC proliferative response to immune-mediated injury. In contrast, p21 does not alter the apoptotic response, resulting in a delayed resolution in nephritic p21-/-mice.",
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AU - Monkawa, Toshiaki

AU - Pippin, Jeffrey

AU - Yo, Yoshikage

AU - Kopp, Jeffrey B.

AU - Alpers, Charles E.

AU - Shankland, Stuart J.

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N2 - Background: Mesangial cell (MC) proliferation underlies increased matrix accumulation in glomerulonephritis (GN), and the resolution of MC proliferation occurs largely through apoptosis. Proliferation and apoptosis are controlled by specific cell cycle proteins, where cyclin-dependent kinase (CDK) inhibitors such as p21 bind target cyclin-CDK complexes. However, the role of p21 in acute mesangial proliferative GN is not known. This study was conducted to test the hypothesis that p21 regulates MC proliferation and apoptosis in anti-MC serum-induced GN. Methods: Age and sex matched wild-type (p21+/+) and p21-deficient (p21-/-) mice were injected with sheep anti-MC serum. Renal function (BUN, urinary albumin excretion), histology, DNA synthesis (BrdU. Ki-67) and apoptosis (TUNEL) were quantified at day 6 and day 12 (n = 6-8/time point). Results: In p21+/+ mice, anti-MC-serum induced mild MC proliferative GN, and glomerular p21 expression was increased. Renal function was worse in nephric p21-/- mice. PAS and silver staining revealed that p21-/- mice had typical features of MC proliferative GN with focal segmental tuft necrosis, focal mesangiolysis and focal mesangial hypercellularity. Occasional features of podocyte injury (swelling, vacuolization) were noted. Double immunostaining confirmed increased mesangial cell DNA synthesis in nephritic p21-/- mice at day 6. In contrast, there was no difference in glomerular apoptosis in nephritic p21+/+ and p21-/-mice at each time point. Glomerular lesions were accompanied by severe glomerular and tubulointerstitial fibrosis in p21-/- mice. Conclusions: This data shows that the CDK-inhibitor p21 regulates the MC proliferative response to immune-mediated injury. In contrast, p21 does not alter the apoptotic response, resulting in a delayed resolution in nephritic p21-/-mice.

AB - Background: Mesangial cell (MC) proliferation underlies increased matrix accumulation in glomerulonephritis (GN), and the resolution of MC proliferation occurs largely through apoptosis. Proliferation and apoptosis are controlled by specific cell cycle proteins, where cyclin-dependent kinase (CDK) inhibitors such as p21 bind target cyclin-CDK complexes. However, the role of p21 in acute mesangial proliferative GN is not known. This study was conducted to test the hypothesis that p21 regulates MC proliferation and apoptosis in anti-MC serum-induced GN. Methods: Age and sex matched wild-type (p21+/+) and p21-deficient (p21-/-) mice were injected with sheep anti-MC serum. Renal function (BUN, urinary albumin excretion), histology, DNA synthesis (BrdU. Ki-67) and apoptosis (TUNEL) were quantified at day 6 and day 12 (n = 6-8/time point). Results: In p21+/+ mice, anti-MC-serum induced mild MC proliferative GN, and glomerular p21 expression was increased. Renal function was worse in nephric p21-/- mice. PAS and silver staining revealed that p21-/- mice had typical features of MC proliferative GN with focal segmental tuft necrosis, focal mesangiolysis and focal mesangial hypercellularity. Occasional features of podocyte injury (swelling, vacuolization) were noted. Double immunostaining confirmed increased mesangial cell DNA synthesis in nephritic p21-/- mice at day 6. In contrast, there was no difference in glomerular apoptosis in nephritic p21+/+ and p21-/-mice at each time point. Glomerular lesions were accompanied by severe glomerular and tubulointerstitial fibrosis in p21-/- mice. Conclusions: This data shows that the CDK-inhibitor p21 regulates the MC proliferative response to immune-mediated injury. In contrast, p21 does not alter the apoptotic response, resulting in a delayed resolution in nephritic p21-/-mice.

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