Depletion of cyclic-GMP levels and inhibition of cGMP-dependent protein kinase activate p21Cip1 /p27Kip1 pathways and lead to renal fibrosis and dysfunction.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
Subhankar DasKailash N Pandey

Abstract

Cell-cycle regulatory proteins (p21Cip1 /p27Kip1 ) inhibit cyclin and cyclin-dependent kinase (CDK) complex that promotes fibrosis and hypertrophy. The present study examined the role of CDK blockers, p21Cip1 /p27Kip1 in the progression of renal fibrosis and dysfunction using Npr1 (encoding guanylyl cyclase/natriuretic peptide receptor-A, GC-A/NPRA) gene-knockout (0-copy; Npr1-/- ), 2-copy (Npr1+/+ ), and 4-copy (Npr1++/++ ) mice treated with GC inhibitor, A71915 and cGMP-dependent protein kinase (cGK) inhibitor, (Rp-8-Br-cGMPS). A significant decrease in renal cGMP levels and cGK activity was observed in 0-copy mice and A71915- and Rp-treated 2-copy and 4-copy mice compared with controls. An increased phosphorylation of Erk1/2, p38, p21Cip1 , and p27Kip1 occurred in 0-copy and A71915-treated 2-copy and 4-copy mice, while Rp treatment caused minimal changes than controls. Pro-inflammatory (TNF-α, IL-6) and pro-fibrotic (TGF-β1) cytokines were significantly increased in plasma and kidneys of 0-copy and A71915-treated 2-copy mice, but to lesser extent in 4-copy mice. Progressive renal pathologies, including fibrosis, mesangial matrix expansion, and tubular hypertrophy were observed in 0-copy and A71915-treated 2-copy and 4-copy m...Continue Reading

References

Mar 15, 1981·Analytical Biochemistry·I S JamallS S Que Hee
Jul 14, 1995·The Journal of Biological Chemistry·M Karin
Jun 16, 1995·The Journal of Biological Chemistry·A Misra-PressP J Stork
Apr 26, 1994·Proceedings of the National Academy of Sciences of the United States of America·O Smithies, H S Kim
Mar 1, 1996·The American Journal of Physiology·S Ernest, E Bello-Reuss
Jan 21, 1997·Proceedings of the National Academy of Sciences of the United States of America·K M Pumiglia, S J Decker
Feb 7, 1998·Proceedings of the National Academy of Sciences of the United States of America·P M OliverN Maeda
Mar 14, 1998·Proceedings of the National Academy of Sciences of the United States of America·M ChengM F Roussel
Apr 16, 1998·Proceedings of the National Academy of Sciences of the United States of America·P M OliverO Smithies
Jul 31, 1998·The New England Journal of Medicine·E R LevinW K Samson
Jan 28, 1999·Biochemical and Biophysical Research Communications·S IshizukaS Horikawa
Jul 8, 1999·Nature Medicine·J S Sebolt-LeopoldA R Saltiel
Aug 17, 2000·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·K Roovers, R K Assoian
Sep 13, 2001·American Journal of Physiology. Renal Physiology·S J ShiK N Pandey
Apr 19, 2002·Journal of the American Society of Nephrology : JASN·Toshiaki MonkawaStuart J Shankland
Jun 26, 2002·The Journal of Biological Chemistry·Darren E CasteelRenate B Pilz
Jan 14, 2003·The Journal of Biological Chemistry·Vincent SauzeauPierre Pacaud
Jun 26, 2003·American Journal of Physiology. Renal Physiology·Shang-Jin ShiKailash N Pandey
Jul 12, 2003·The Journal of Biological Chemistry·Nathan AirhartMichael Silberbach
Feb 27, 2004·American Journal of Physiology. Cell Physiology·Natasha C BrownerThomas M Lincoln
Jun 19, 2004·American Journal of Physiology. Regulatory, Integrative and Comparative Physiology·Shaohua ChangMichael E DiSanto
Sep 10, 2004·American Journal of Physiology. Cell Physiology·Asha JacobNajma Begum
Sep 25, 2004·FEBS Letters·A GeiselhöringerJ Schlossmann

❮ Previous
Next ❯

Citations


❮ Previous
Next ❯

Methods Mentioned

BETA
cytokine assay
Assay
biopsies
PCR
ELISA
protein kinase assay

Software Mentioned

MxPro
GraphPad PRISM
REST2009
MxPro QPCR
ImagePro Plus
GraphPad

Related Concepts

Related Feeds

Cell Cycle Pathways

Cell cycle is a complex process regulated by several signal transduction pathways and enzymes. Here is the latest research on regulation of cell cycle and cell cycle pathways.

Cell Checkpoints & Regulators

Cell cycle checkpoints are a series of complex checkpoint mechanisms that detect DNA abnormalities and ensure that DNA replication and repair are complete before cell division. They are primarily regulated by cyclins, cyclin-dependent kinases, and the anaphase-promoting complex/cyclosome. Here is the latest research.