title: Podocyte hypertrophy precedes apoptosis under experimental diabetic conditions.
abstract: Podocyte hypertrophy and apoptosis are two hallmarks of diabetic glomeruli, but the sequence in which these processes occur remains a matter of debate. Here we investigated the effects of inhibiting hypertrophy on apoptosis, and vice versa, in both podocytes and glomeruli, under diabetic conditions. Hypertrophy and apoptosis were inhibited using an epidermal growth factor receptor inhibitor (PKI 166) and a pan-caspase inhibitor (zAsp-DCB), respectively. We observed significant increases in the protein expression of p27, p21, phospho-eukaryotic elongation factor 4E-binding protein 1, and phospho-p70 S6 ribosomal protein kinase, in both cultured podocytes exposed to high-glucose (HG) medium, and streptozotocin-induced diabetes mellitus (DM) rat glomeruli. These increases were significantly inhibited by PKI 166, but not by zAsp-DCB. In addition, the amount of protein per cell, the relative cell size, and the glomerular volume were all significantly increased under diabetic conditions, and these changes were also blocked by treatment with PKI 166, but not zAsp-DCB. Increased protein expression of cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase, together with increased Bax/Bcl-2 ratios, were also observed in HG-stimulated podocytes and DM glomeruli. Treatment with either zAsp-DCB or PKI 166 resulted in a significant attenuation of these effects. Both PKI 166 and zAsp-DCB also inhibited the increase in number of apoptotic cells, as assessed by Hoechst 33342 staining and TUNEL assay. Under diabetic conditions, inhibition of podocyte hypertrophy results in attenuated apoptosis, whereas blocking apoptosis has no effect on podocyte hypertrophy, suggesting that podocyte hypertrophy precedes apoptosis.
authors.affiliation: Department of Internal Medicine, College of Medicine, Brain Korea 21 for Medical Science, Severance Biomedical Science Institute, Yonsei University, 134 Shinchon-Dong Seodaemoon-Gu, Seoul, 120-752, Korea.
authors.forename: Sun Ha
authors.initials: SH
authors.lastname: Lee
authors.forename: Sung Jin
authors.initials: SJ
authors.lastname: Moon
authors.forename: Jisun
authors.initials: J
authors.lastname: Paeng
authors.forename: Hye-Young
authors.initials: HY
authors.lastname: Kang
authors.forename: Bo Young
authors.initials: BY
authors.lastname: Nam
authors.forename: Seonghun
authors.initials: S
authors.lastname: Kim
authors.forename: Chan Ho
authors.initials: CH
authors.lastname: Kim
authors.forename: Mi Jung
authors.initials: MJ
authors.lastname: Lee
authors.forename: Hyung Jung
authors.initials: HJ
authors.lastname: Oh
authors.forename: Jung Tak
authors.initials: JT
authors.lastname: Park
authors.forename: Seung Hyeok
authors.initials: SH
authors.lastname: Han
authors.forename: Tae-Hyun
authors.initials: TH
authors.lastname: Yoo
authors.forename: Shin-Wook
authors.initials: SW
authors.lastname: Kang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006984:Hypertrophy / Q000378:metabolism / Q000473:pathology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D013311:Streptozocin
chemical_list: D051017:Apoptosis Regulatory Proteins; D061945:Caspase Inhibitors; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C093260:benzyloxycarbonyl-Asp-CH2OC(O)-2,6-dichlorobenzene; D001224:Aspartic Acid; D013311:Streptozocin; C410026:PKI 166; C483803:Egfr protein, rat; D066246:ErbB Receptors; D053148:Caspase 3