Activation of the receptor for advanced glycation end products induces nuclear inhibitor of protein phosphatase-1 suppression.
The activation of the receptor for advanced glycation end products (RAGE) is involved in the development of diabetic nephropathy. Analysis of protein phosphatase-1 indicated that advanced glycation end products did not affect its expression, but increased its phosphatase activity. Using differential display analysis we previously demonstrated that stimulation of RAGE in podocytes modulates the expression of numerous genes, among others nuclear inhibitor of protein phosphatase-1 (NIPP1). Here we found that silencing of NIPP1 induced podocyte hypertrophy, cell cycle arrest, and significantly increased protein phosphatase-1 activity. NIPP1 downregulation was associated with increased p27(Kip1) protein expression. Reporter assays revealed a transcriptional activation of nuclear factor-κB in podocytes after suppression of NIPP1. The protein level of NIPP1 was also significantly reduced in podocytes of diabetic mice. Blocking the RAGE in vivo by a soluble analog elevated the NIPP1 protein in podocytes of diabetic mice. Thus, activation of the RAGE by advanced glycation end products or other ligands suppresses NIPP1 expression in diabetic nephropathy, contributes to podocyte hypertrophy, and glomerular inflammation.
Department of Internal Medicine III, University Hospital Jena, Jena, Germany.
Marita
M
Liebisch
Department of Internal Medicine III, University Hospital Jena, Jena, Germany.
Tzvetanka
T
Bondeva
Department of Internal Medicine III, University Hospital Jena, Jena, Germany.
Sybille
S
Franke
Nephropathology Department, Institute of Pathology, Erlangen-Nürnberg University, Erlangen, Germany.
Christoph
C
Daniel
Nephropathology Department, Institute of Pathology, Erlangen-Nürnberg University, Erlangen, Germany.
Kerstin
K
Amann
Department of Internal Medicine III, University Hospital Jena, Jena, Germany.
Gunter
G
Wolf
D000818:Animals; D017209:Apoptosis; D016022:Case-Control Studies; D059447:Cell Cycle Checkpoints; D049108:Cell Enlargement; D049109:Cell Proliferation; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D004722:Endoribonucleases / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000378:metabolism / Q000494:pharmacology
C493961:Cdkn1b protein, mouse; D017127:Glycation End Products, Advanced; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D000067759:Receptor for Advanced Glycation End Products; C081628:advanced glycation end products-bovine serum albumin; C021042:protein phosphatase inhibitor-1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D012710:Serum Albumin, Bovine; C048496:N(6)-carboxymethyllysine; D004722:Endoribonucleases; D010749:Phosphoprotein Phosphatases; C097081:PPP1R8 protein, human; D008239:Lysine