Glucose and diabetes: effects on podocyte and glomerular p38MAPK, heat shock protein 25, and actin cytoskeleton.
Phosphorylated p38 (pp38) mitogen-activated protein kinase (MAPK) regulates heat shock protein 25 (HSP25), stabilizing fibrillar actin (FA) and preventing cleavage to G-actin (GA). Cultured podocytes (Pods) were exposed to glucose (5.5-50 mM)+/-p38MAPK inhibitor SB202190 (SB) or control SB202474 to assess the effects on FA/GA and Pod structure. The relationship of p38MAPK with in vivo Pod structure and albuminuria (Ualb) was assessed in rats with streptozotocin (SZ)-induced diabetes (DM) for 1 week, 1 month, and 4 months. High glucose induced concentration-dependent increases in pp38MAPK and phosphorylated HSP25 (pHSP25) maintained actin cytoskeleton. Inhibition by SB diminished pp38MAPK and pHSP25, decreased FA/GA, and altered FA and GA immunohistochemical appearance. In SZ-DM, glomerular pp38MAPK and biphosphorylated HSP25 were increased after 1 week, declining at 1 month, and at or below C values at 4 months. Glomerular FA/GA in DM was normal at 1 week, declining at 1 month, and low at 4 months. Ualb/creatinine was similar in DM vs C at 1 week, and increased at 1 and 4 months. Morphometry demonstrated progressively diminishing slit pore density in DM over time, denoting evolving effacement. There were strong correlations between slit membrane density and both glomerular biphosphorylated HSP25 and ln Ualb/cr ratio. The data suggest that increased pp38MAPK and pHSP25 comprise an acute adaptation to glycemic stress. Later depletion of DM may contribute to Pod structural alterations and Ualb.
Dai
T
T
Harbor-UCLA Los Angeles Biomedical Research Institute, 1124 West Carson Street, Torrance, CA 90502, USA.
Natarajan
R
R
Nast
C C
CC
LaPage
J
J
Chuang
P
P
Sim
J
J
Tong
L
L
Chamberlin
M
M
Wang
S
S
Adler
S G
SG
D000199:Actins / Q000378:metabolism; D000419:Albuminuria / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000378:metabolism; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000199:Actins; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C486113:Hsbp1 protein, mouse; C486114:Hspb1 protein, rat; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose