Ouabain protects against adverse developmental programming of the kidney.
The kidney is extraordinarily sensitive to adverse fetal programming. Malnutrition, the most common form of developmental challenge, retards the formation of functional units, the nephrons. The resulting low nephron endowment increases susceptibility to renal injury and disease. Using explanted rat embryonic kidneys, we found that ouabain, the Na,K-ATPase ligand, triggers a calcium-nuclear factor-κB signal, which protects kidney development from adverse effects of malnutrition. To mimic malnutrition, kidneys were serum deprived for 24 h. This resulted in severe retardation of nephron formation and a robust increase in apoptosis. In ouabain-exposed kidneys, no adverse effects of serum deprivation were observed. Proof of principle that ouabain rescues development of embryonic kidneys exposed to malnutrition was obtained from studies on pregnant rats given a low-protein diet and treated with ouabain or vehicle throughout pregnancy. Thus, we have identified a survival signal and a feasible therapeutic tool to prevent adverse programming of kidney development.
Department of Women's and Children's Health, Karolinska Institutet, Stockholm 17176, Sweden.
Juan
J
Li
Georgiy R
GR
Khodus
Markus
M
Kruusmägi
Padideh
P
Kamali-Zare
Xiao-Li
XL
Liu
Ann-Christine
AC
Eklöf
Sergey
S
Zelenin
Hjalmar
H
Brismar
Anita
A
Aperia
D000818:Animals; D018753:Diet, Protein-Restricted / Q000009:adverse effects; D005260:Female; D007668:Kidney / Q000187:drug effects* / Q000196:embryology* / Q000378:metabolism; D044342:Malnutrition / Q000503:physiopathology; D010042:Ouabain / Q000494:pharmacology*; D051762:PAX2 Transcription Factor / Q000235:genetics; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025721:WT1 Proteins / Q000235:genetics
D051762:PAX2 Transcription Factor; C551986:PAX2 protein, rat; D025721:WT1 Proteins; D010042:Ouabain