IL-6/Smad2 signaling mediates acute kidney injury and regeneration in a murine model of neonatal hyperoxia.

Prematurity is linked to incomplete nephrogenesis and risk of chronic kidney diseases (CKDs). Oxygen is life-saving in that context but induces injury in numerous organs. Here, we studied the structural and functional impact of hyperoxia on renal injury and its IL-6 dependency. Newborn wild-type (WT) and IL-6 knockout (IL-6) mice were exposed to 85% O for 28 d, followed by room air until postnatal d (P) 70. Controls were in room air throughout life. At P28, hyperoxia reduced estimated kidney cortex area (KCA) in WT; at P70, KCA was greater, number of glomeruli was fewer, fractional potassium excretion was higher, and glomerular filtration rate was slightly lower than in controls. IL-6 mice were protected from these changes after hyperoxia. Mechanistically, the acute renal injury phase (P28) showed in WT but not in IL-6 mice an activation of IL-6 (signal transducer and activator of transcription 3) and TGF-β [mothers against decapentaplegic homolog (Smad)2] signaling, increased inflammatory markers, disrupted mitochondrial biogenesis, and reduced tubular proliferation. Regenerative phase at P70 was characterized by tubular proliferation in WT but not in IL-6 mice. These data demonstrate that hyperoxia increases the risk of CKD through a novel IL-6-Smad2 axis. The amenability of these pathways to pharmacological approaches may offer new avenues to protect premature infants from CKD.-Mohr, J., Voggel, J., Vohlen, C., Dinger, K., Dafinger, C., Fink, G., Göbel, H., Liebau, M. C., Dötsch, J., Alejandre Alcazar, M. A. IL-6/Smad2 signaling mediates acute kidney injury and regeneration in a murine model of neonatal hyperoxia.