High glucose promotes nascent nephron apoptosis via NF-kappaB and p53 pathways.
A hyperglycemic environment in utero reduces kidney size and nephron number due to nascent nephron apoptosis. However, the underlying mechanisms are incompletely understood. The present study investigated whether the nascent nephron apoptosis promoted by high glucose is mediated via the transcription factor NF-κB and p53 signaling pathways. Neonatal mouse kidneys from the offspring of nondiabetic, diabetic, and insulin-treated diabetic dams were used for in vivo studies, and MK4 cells, an embryonic metanephric mesenchymal (MM) cell line, were used for in vitro studies. Neonatal kidneys of the offspring of diabetic mothers exhibited an increased number of apoptotic cells and reactive oxygen species (ROS) generation, enhanced NF-κB activation, and nuclear translocation of its subunits (p50 and p65 subunits) as well as phosphorylation (Ser 15) of p53 compared with kidneys of offspring of nondiabetic mothers. Insulin treatment of diabetic dams normalized these parameters in the offspring. In vitro, high-glucose (25 mM) induced ROS generation and significantly increased MK4 cell apoptosis and caspase-3 activity via activation of NF-κB pathway, with p53 phosphorylation and nuclear translocation compared with normal glucose (5 mM). These changes in a high-glucose milieu were prevented by transient transfection of small interfering RNAs for dominant negative IκBα or IKK or p53. Our data demonstrate that high glucose-induced nascent nephron apoptosis is mediated, at least in part, via ROS generation and the activation of NF-κB and p53 pathways.
Université de Montréal, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, CRCHUM, Hôpital Hôtel-Dieu, Pavillon Masson, 3850 Saint-Urbain St., Montreal, Quebec, Canada H2W 1T7.
Yun-Wen
YW
Chen
Isabelle
I
Chenier
Shiao-Ying
SY
Chang
Stella
S
Tran
Julie R
JR
Ingelfinger
Shao-Ling
SL
Zhang
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D005260:Female; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology*; D007328:Insulin / Q000627:therapeutic use; D007668:Kidney / Q000002:abnormalities; D051379:Mice; D016328:NF-kappa B / Q000502:physiology*; D052002:NF-kappa B p50 Subunit / Q000096:biosynthesis; D009399:Nephrons / Q000002:abnormalities / Q000187:drug effects*; D011247:Pregnancy; D011254:Pregnancy in Diabetics / Q000188:drug therapy / Q000503:physiopathology; D051996:Transcription Factor RelA / Q000096:biosynthesis; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D007328:Insulin; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; D005947:Glucose