Signaling pathways and late-onset gene induction associated with renal mesangial cell hypertrophy.
In chronic diseases such as diabetes mellitus, continuous stress stimuli trigger a persistent, self-reinforcing reprogramming of cellular function and gene expression that culminates in the pathological state. Late-onset, stable changes in gene expression hold the key to understanding the molecular basis of chronic diseases. Renal failure is a common, but poorly understood complication of diabetes. Diabetic nephropathy begins with mesangial cell hypertrophy and hyperplasia, combined with excess matrix deposition. The vasoactive peptide endothelin promotes the mesangial cell hypertophy characteristic of diabetic nephropathy. In this study, we examined the signaling pathways and changes in gene expression required for endothelin-induced mesangial cell hypertrophy. Transcriptional profiling identified seven genes induced with slow kinetics by endothelin. Of these, p8, which encodes a small basic helix-loop-helix protein, was most strongly and stably induced. p8 is also induced in diabetic kidney. Mesangial cell hypertrophy and p8 induction both require activation of the ERK, JNK/SAPK and PI-3-K pathways. Small interfering RNA (siRNA)-mediated RNA interference indicates that p8 is required for endothelin-induced hypertrophy. Thus, p8 is a novel marker for diabetic renal hypertrophy.
Goruppi
Sandro
S
Diabetes Research Laboratory, Department of Medicine, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Bonventre
Joseph V
JV
Kyriakis
John M
JM
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019332:Endothelin-1 / Q000494:pharmacology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005819:Genetic Markers; D005920:Glomerular Mesangium / Q000378:metabolism* / Q000473:pathology*; D006133:Growth Substances / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006984:Hypertrophy; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009363:Neoplasm Proteins; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D015398:Signal Transduction; D015533:Transcriptional Activation; D048051:p38 Mitogen-Activated Protein Kinases
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D019332:Endothelin-1; D005819:Genetic Markers; D006133:Growth Substances; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C491643:NUPR1 protein, human; C109741:Nupr1 protein, rat