Kidney Injuries and Evolution of Chronic Kidney Diseases Due to Neonatal Hyperoxia Exposure Based on Animal Studies

Abstract

Preterm birth interrupts the development and maturation of the kidneys during the critical growth period. The kidneys can also exhibit structural defects and functional impairment due to hyperoxia, as demonstrated by various animal studies. Furthermore, hyperoxia during nephrogenesis impairs renal tubular development and induces glomerular and tubular injuries, which manifest as renal corpuscle enlargement, renal tubular necrosis, interstitial inflammation, and kidney fibrosis. Preterm birth along with hyperoxia exposure induces a pathological predisposition to chronic kidney disease. Hyperoxia-induced kidney injuries are influenced by several molecular factors, including hypoxia-inducible factor-1α and interleukin-6/Smad2/transforming growth factor-β, and Wnt/β-catenin signaling pathways; these are key to cell proliferation, tissue inflammation, and cell membrane repair. Hyperoxia-induced oxidative stress is characterized by the attenuation or the induction of multiple molecular factors associated with kidney damage. This review focuses on the molecular pathways involved in the pathogenesis of hyperoxia-induced kidney injuries to establish a framework for potential interventions.

Keywords: chronic kidney disease; hyperoxia; kidney fibrosis; kidney injury; nephrogenesis; prematurity.

Figure 1

Schematic of the mechanism of hyperoxia-induced kidney injury and renal interstitial fibrosis. Hyperoxia induces reactive oxidative stress; prolyl hydroxylases domain enzymes, which downregulate HIF-1α, upregulate IL-6, and trigger the activation of 8-OHdG, bind to the plasma membrane receptor RAGE and TLR-4, thereby enhancing the generation of ROS. This regulates the inflammatory transcription factors NF-κB, IL-1β, and MPO, which induce Wnt ligands and subsequently activate β-catenin. The activation of β-catenin triggers podocyte injury through dedifferentiation and mesenchymal transition. The downregulation of HIF-1α suppresses MAPK and ERK, thereby reducing catalase levels. The reduction of catalase triggers proximal tubular injury and impairs glomerular development. The upregulation of IL-6 triggers the activation of phosphorylated Smad2. This in turn induces the phosphorylation of STAT3, the activation of TGF-β1, and the formation of alpha SMA, PAL1, CTGF, and collagen IV. The activation of α-SMA and collagen IV subsequently induces renal mesangial and interstitial fibrosis. Abbreviations: PHD: prolyl hydroxylases domain enzyme; IL-6: interleukin-6; PAI-1: plasminogen activator inhibitor-1; CTGF: connective tissue growth factor; HIF-1α: hypoxia inducible factor-1α; 8-OHdG: 8-hydroxydeoxyguanosine; MPO: myeloperoxidase; TLR4: toll like receptor; IL-1β: interleukin-1β; MAPK/ERK: mitogen-activated protein kinase, extracellular signal-regulated kinase; TNF-α: tumor necrosis factor-α; STAT3: signal transducer and activator of transcription3; TGF-β1: transforming growth factor-β1; alpha SMA: alpha smooth muscle actin.