Activation of the receptor for advanced glycation end products induces nuclear inhibitor of protein phosphatase-1 suppression

Marita Liebisch; Tzvetanka Bondeva; Sybille Franke; Christoph Daniel; Kerstin Amann; Gunter Wolf

doi:10.1038/ki.2014.3

Activation of the receptor for advanced glycation end products induces nuclear inhibitor of protein phosphatase-1 suppression

Kidney Int. 2014 Jul;86(1):103-17. doi: 10.1038/ki.2014.3. Epub 2014 Jan 29.

Authors

Marita Liebisch¹, Tzvetanka Bondeva¹, Sybille Franke¹, Christoph Daniel², Kerstin Amann², Gunter Wolf¹

Affiliations

¹ Department of Internal Medicine III, University Hospital Jena, Jena, Germany.
² Nephropathology Department, Institute of Pathology, Erlangen-Nürnberg University, Erlangen, Germany.

PMID: 24476693
DOI: 10.1038/ki.2014.3

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Case-Control Studies
Cell Cycle Checkpoints
Cell Enlargement
Cell Proliferation
Cells, Cultured
Cyclin-Dependent Kinase Inhibitor p27 / metabolism
Diabetic Nephropathies / etiology
Diabetic Nephropathies / genetics
Diabetic Nephropathies / metabolism
Down-Regulation
Endoribonucleases / metabolism
Glycation End Products, Advanced / metabolism
Glycation End Products, Advanced / pharmacology
Humans
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism*
Lysine / analogs & derivatives
Lysine / metabolism
Mice
NF-kappa B / metabolism
Necrosis
Phosphoprotein Phosphatases / metabolism
Podocytes / drug effects
Podocytes / metabolism*
Podocytes / pathology
RNA, Messenger / genetics
RNA, Messenger / metabolism
RNA, Small Interfering / genetics
RNA-Binding Proteins / metabolism
Receptor for Advanced Glycation End Products / metabolism*
Serum Albumin, Bovine / metabolism
Serum Albumin, Bovine / pharmacology

Substances

Cdkn1b protein, mouse
Glycation End Products, Advanced
Intracellular Signaling Peptides and Proteins
NF-kappa B
RNA, Messenger
RNA, Small Interfering
RNA-Binding Proteins
Receptor for Advanced Glycation End Products
advanced glycation end products-bovine serum albumin
protein phosphatase inhibitor-1
Cyclin-Dependent Kinase Inhibitor p27
Serum Albumin, Bovine
N(6)-carboxymethyllysine
Endoribonucleases
Phosphoprotein Phosphatases
PPP1R8 protein, human
Lysine