CXCL10 deficiency protects against hyperoxia-induced inflammation and cellular stress in kidneys of newborn mice

Prematurity and life-saving respiratory therapy increase the risk of kidney injury and chronic kidney disease. We previously showed that hyperoxia does not only induce macrophage-associated lung injury with increased expression of the chemokine interferon-gamma induced protein 10 (CXCL10) in neonatal mice, but also kidney maturation via inflammation. Since CXCL10 contributes to the pathogenesis of kidney disease through chemoattraction of immune cells, we investigated the impact of CXCL10 deletion on the kidney after postnatal hyperoxia. To this end, wild-type (WT; C57BL6J) and Cxcl10-knockout mice (Cxcl10-/-; B6.129S4-Cxcl10^tm1Adl/J) were exposed to 85% O₂ (HYX) or 21% O₂ (NOX) from birth to postnatal day (P)14. First, Cxcl10-/- were protected against the HYX-induced increase of interleukin-1β (ll-1β) and Il6 at P14. In addition, this CXCL10 deficiency mitigated the cellular stress response (Ppargc1a, p53 and Tfam) in kidneys after HYX. Subsequent immunoblot analysis revealed a protection of Cxcl10-/- against the reduced expression of PGC1α (mitochondrial biogenesis) after HYX. Second, reduced gene expression profiles of TGF-β target genes (Serpine1, Collagen4, Elastin and Connective tissue growth factor [Ctgf]) in kidneys of Cxcl10-/- mice were partially independent of HYX. Immunoblot confirmed reduced CTGF in Cxcl10-/- after HYX. In conclusion, our data show that neonatal hyperoxia leads to a CXCL10-mediated inflammatory cellular stress response with profibrotic processes in the kidney. These data indicate that targeting pulmonary inflammation caused by hyperoxia might be beneficial for the renal outcome in preterm infants.