Advanced glycation end-products suppress neuropilin-1 expression in podocytes.
Advanced glycation end products (AGEs) have been linked to the pathogenesis of diabetic nephropathy. Here we tested the effect of AGE-modified bovine serum albumin (AGE-BSA) on differentiated mouse podocytes in culture. Differential display and real-time PCR analyses showed that in addition to neuropilin-1, the entire signaling receptor complex of neuropilin-2, semaphorin-3A, and plexin-A1, was significantly reduced by AGE-BSA as was neuropilin-1 protein. The effect was specific for podocytes compared to isolated mesangial and tubular epithelial cells. Further, AGE-BSA was not toxic to podocytes. Neuropilin-1 expression was decreased in glomeruli of diabetic db/db mice compared to their non-diabetic littermates. Transcripts of both neuropilins were found to be decreased in renal biopsies from patients with diabetic nephropathy compared to transplant donors. Podocyte migration was inhibited by AGE-BSA with similar results found in the absence of AGE-BSA when neuropilin-1 expression was down-regulated by siRNA. In contrast, podocyte migration was stimulated by overexpression of neuropilin-1 even in the presence of AGE-BSA. Our study shows that AGE-BSA inhibited podocyte migration by down-regulating neuropilin-1. The decreased migration could lead to adherence of uncovered areas of the glomerular basement membrane to Bowman's capsule contributing to focal glomerulosclerosis.
Bondeva
Tzvetanka
T
Klinik für Innere Medizin III, Friedrich-Schiller-University, Jena, Germany.
Rüster
Christiane
C
Franke
Sybille
S
Hammerschmid
Elke
E
Klagsbrun
Michael
M
Cohen
Clemens D
CD
Wolf
Gunter
G
D000818:Animals; D003920:Diabetes Mellitus; D003928:Diabetic Nephropathies / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects*; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D006801:Humans; D007668:Kidney / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics; D039942:Neuropilin-1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D039943:Neuropilin-2 / Q000235:genetics; D050199:Podocytes / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface / Q000235:genetics; D040121:Semaphorin-3A / Q000235:genetics; D012710:Serum Albumin, Bovine / Q000494:pharmacology*
D017127:Glycation End Products, Advanced; D009419:Nerve Tissue Proteins; D039943:Neuropilin-2; C492114:Plxna1 protein, mouse; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D040121:Semaphorin-3A; C081628:advanced glycation end products-bovine serum albumin; D039942:Neuropilin-1; D012710:Serum Albumin, Bovine