Glomerular aging in females is a multi-stage reversible process mediated by phenotypic changes in progenitors.
The glomeruli of postmenopausal C57BL6 mice, and age-matched males, show progressive hypertrophy and glomerulosclerosis. We asked whether this was a multistage process, was due to alterations in glomerular progenitors, and was reversible in female mice. Using cross bone marrow transplants (BMT) between young and old females, we found that BMT delivered a phenotype that was donor age-specific. The fact that lesions in young recipients were more severe if the donors were in late rather than early menopause suggested that new progenitor phenotypes had appeared. Postmenopausal recipients of BMT from young donors had reduced glomerular hypertrophy and sclerosis, implying that the aging lesions in females were reversible and that progenitors, rather than the local environment, determined the glomerular profile. The altered phenotype included increased extracellular matrix synthesis and decreased matrix metalloproteinase-2 levels as well as cell hypertrophy. The mechanism of the cellular hypertrophy was due to uncoupling of hypertrophy from proliferation, resulting from elevated p27 levels. Thus, glomerular hypertrophy and sclerosis in aging females is a multistage process, is reversible, and may be determined by the phenotype of bone marrow-derived progenitor cells.
Feng
Zheng
Z
Department of Medicine, Division of Nephrology, Vascular Biology Institute, University of Miami School of Medicine, Florida, USA. feng.zheng@mssm.edu
Plati
Anna Rita
AR
Cheng
Qing-li
QL
Berho
Mariana
M
Banerjee
Anita
A
Potier
Mylene
M
Jy
Wen-che
WC
Koff
Andrew
A
Striker
Liliane J
LJ
Striker
Gary E
GE
D000375:Aging; D000818:Animals; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005260:Female; D005434:Flow Cytometry; D005920:Glomerular Mesangium / Q000166:cytology / Q000502:physiology*; D006984:Hypertrophy; D007124:Immunoenzyme Techniques; D007678:Kidney Glomerulus / Q000502:physiology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D012598:Sclerosis; D013234:Stem Cells / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D020778:Matrix Metalloproteinase 2