Regulation of podocyte survival and endoplasmic reticulum stress by fatty acids

TY - JOUR

T1 - Regulation of podocyte survival and endoplasmic reticulum stress by fatty acids

AU - Sieber, Jonas

AU - Lindenmeyer, Maja Tamara

AU - Kampe, Kapil

AU - Campbell, Kirk Nicholas

AU - Cohen, Clemens David

AU - Hopfer, Helmut

AU - Mundel, Peter

AU - Jehle, Andreas Werner

PY - 2010/10

Y1 - 2010/10

N2 - Apoptosis of podocytes is considered critical in the pathogenesis of diabetic nephropathy (DN). Free fatty acids (FFAs) are critically involved in the pathogenesis of diabetes mellitus type 2, in particular the regulation of pancreatic β cell survival. The objectives of this study were to elucidate the role of palmitic acid, palmitoleic, and oleic acid in the regulation of podocyte cell death and endoplasmic reticulum (ER) stress. We show that palmitic acid increases podocyte cell death, both apoptosis and necrosis of podocytes, in a dose and time-dependent fashion. Palmitic acid induces podocyte ER stress, leading to an unfolded protein response as reflected by the induction of the ER chaperone immunoglobulin heavy chain binding protein (BiP) and proapoptotic C/EBP homologous protein (CHOP) transcription factor. Of note, the monounsaturated palmitoleic and oleic acid can attenuate the palmitic acid-induced upregulation of CHOP, thereby preventing cell death. Similarly, gene silencing of CHOP protects against palmitic acid-induced podocyte apoptosis. Our results offer a rationale for interventional studies aimed at testing whether dietary shifting of the FFA balance toward unsaturated FFAs can delay the progression of DN.

AB - Apoptosis of podocytes is considered critical in the pathogenesis of diabetic nephropathy (DN). Free fatty acids (FFAs) are critically involved in the pathogenesis of diabetes mellitus type 2, in particular the regulation of pancreatic β cell survival. The objectives of this study were to elucidate the role of palmitic acid, palmitoleic, and oleic acid in the regulation of podocyte cell death and endoplasmic reticulum (ER) stress. We show that palmitic acid increases podocyte cell death, both apoptosis and necrosis of podocytes, in a dose and time-dependent fashion. Palmitic acid induces podocyte ER stress, leading to an unfolded protein response as reflected by the induction of the ER chaperone immunoglobulin heavy chain binding protein (BiP) and proapoptotic C/EBP homologous protein (CHOP) transcription factor. Of note, the monounsaturated palmitoleic and oleic acid can attenuate the palmitic acid-induced upregulation of CHOP, thereby preventing cell death. Similarly, gene silencing of CHOP protects against palmitic acid-induced podocyte apoptosis. Our results offer a rationale for interventional studies aimed at testing whether dietary shifting of the FFA balance toward unsaturated FFAs can delay the progression of DN.

KW - Animals

KW - Apoptosis

KW - Caspase 3

KW - Cell Survival

KW - Cells, Cultured

KW - Endoplasmic Reticulum

KW - Fatty Acids, Monounsaturated

KW - Gene Silencing

KW - Mice

KW - Models, Animal

KW - Oleic Acid

KW - Palmitic Acid

KW - Podocytes

KW - Stress, Physiological

KW - Transcription Factor CHOP

KW - Journal Article

KW - Research Support, N.I.H., Extramural

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

U2 - 10.1152/ajprenal.00196.2010

DO - 10.1152/ajprenal.00196.2010

M3 - SCORING: Journal article

C2 - 20668104

VL - 299

SP - F821-9

JO - AM J PHYSIOL-RENAL

JF - AM J PHYSIOL-RENAL

SN - 1931-857X

IS - 4

ER -