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Podocyte hypertrophy precedes apoptosis under experimental diabetic conditions

 Sun Ha Lee  ;  Sung Jin Moon  ;  Jisun Paeng  ;  Hye-Young Kang  ;  Bo Young Nam  ;  Seonghun Kim  ;  Chan Ho Kim  ;  Mi Jung Lee  ;  Hyung Jung Oh  ;  Jung Tak Park  ;  Seung Hyeok Han  ;  Tae-Hyun Yoo  ;  Shin-Wook Kang 
 APOPTOSIS, Vol.20(8) : 1056-1071, 2015 
Journal Title
Issue Date
Animals ; Apoptosis/drug effects* ; Apoptosis Regulatory Proteins/metabolism ; Aspartic Acid/analogs & derivatives ; Aspartic Acid/pharmacology ; Caspase 3/metabolism ; Caspase Inhibitors/pharmacology ; Cells, Cultured ; Diabetes Mellitus, Experimental/chemically induced* ; Gene Expression/drug effects ; Hypertrophy/metabolism ; Hypertrophy/pathology ; Kidney Glomerulus/drug effects ; Kidney Glomerulus/metabolism ; Kidney Glomerulus/pathology ; Male ; Mice ; Podocytes/drug effects ; Podocytes/metabolism ; Podocytes/pathology* ; Protein Kinase Inhibitors/pharmacology ; Pyrimidines/pharmacology ; Pyrroles/pharmacology ; Rats, Sprague-Dawley ; Receptor, Epidermal Growth Factor/antagonists & inhibitors ; Receptor, Epidermal Growth Factor/metabolism ; Streptozocin
Apoptosis ; Caspase ; Diabetic nephropathy ; Epidermal growth factor ; Hypertrophy ; Podocyte
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.
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1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Shin Wook(강신욱) ORCID logo https://orcid.org/0000-0002-5677-4756
Kang, Hye Young(강혜영)
Kim, Seonghun(김성훈)
Kim, Chan Ho(김찬호)
Moon, Sung Jin(문성진)
Park, Jung Tak(박정탁) ORCID logo https://orcid.org/0000-0002-2325-8982
Oh, Hyung Jung(오형중)
Yoo, Tae Hyun(유태현) ORCID logo https://orcid.org/0000-0002-9183-4507
Lee, Mi Jung(이미정)
Lee, Sun Ha(이순하)
Paeng, Ji Sun(팽지선)
Han, Seung Hyeok(한승혁) ORCID logo https://orcid.org/0000-0001-7923-5635
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