Angiotensin II upregulates RAGE expression on podocytes: role of AT2 receptors.
BACKGROUND
Advanced glycation end products (AGEs) play an important role in diabetic nephropathy. The receptor for AGEs, called RAGE, is present on podocytes. We investigated whether angiotensin II (ANG II) modulates RAGE expression on cultured differentiated podocytes.


RESULTS
Cultured podocytes expressed AT1 and AT2 receptors. Surprisingly, ANG II induced RAGE mRNA and protein expression through AT2 receptors. ANG II had no influence on proliferation or protein content of podocytes. The increase in RAGE expression depended on stimulated transcriptional activity. Using various mutant reporter constructs of the RAGE promoter region, it was shown that a NF-kappaB binding site at -1519 was essential for ANG II-induced transcriptional activity. Preincubation with ANG II increased the expression of tumor necrosis factor-alpha mRNA and protein expression induced by AGE, indicating that the ANG II-mediated upregulation of RAGE has functional consequences. AGE-BSA was incorporated into cells as measured by Western blots for N epsilon-carboxymethyllysine, but ANG II did not influence this process. ANG II in the absence or presence of AGE-BSA did not induce apoptosis of podocytes.


CONCLUSIONS
Our study revealed aninteraction between the renin-angiotensin system and the AGE/RAGE axis in podocytes. Since intraglomerular ANG II levels are increased in diabetic nephropathy, this interaction may have pathophysiological consequences for podocyte injury and inflammation associated with the development of diabetic nephropathy.
Rüster
Christiane
C
Klinik für Innere Medizin III, Friedrich Schiller University, Jena, Germany.
Bondeva
Tzvetanka
T
Franke
Sybille
S
Tanaka
Nobushige
N
Yamamoto
Hiroshi
H
Wolf
Gunter
G
D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002478:Cells, Cultured; D017127:Glycation End Products, Advanced / Q000378:metabolism; D051379:Mice; D050199:Podocytes / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000378:metabolism; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
D017127:Glycation End Products, Advanced; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha; C081628:advanced glycation end products-bovine serum albumin; D000804:Angiotensin II; D012710:Serum Albumin, Bovine