Figure 3.

Under physiological conditions little transferrin bound (TBI) and non-transferrin bound iron (NTBI) is filtered by the glomerular assembly and is reabsorbed and cycled by the proximal tubular cells (PTEC). However, in LN, glomerular injury results in an increased leakage of TBI and NTBI, which can be reabsorbed by the PTEC via TfR1, ZIP8/14, and MCEC. While TfR1 is regulated by the IRP-IRE system, ZIP8/14, and MCEC are not and can continue to absorb the leaking TBI and NTBI to iron overload the PTEC. This can overwhelm the heavy chain ferritin (FtH) iron binding capacity, leading to release of labile iron and render the PTEC susceptible to ROS mediated injury and lipid peroxidation. The glomerulopathy associated protein overload (e.g., albumin) and lupus autoantibodies can independently induce ROS in the PTEC and activate ROS sensitive inflammatory pathways. The accumulated iron can catalyze ROS formation via the Fenton reaction and exacerbate the inflammatory phenotype of the PTEC to worsen tubulointerstitial injury and accelerate the progression to renal failure. TfR1, transferrin receptor 1; MCEC, megalin cubulin endocytic complex; FtH, heavy chain ferritin; ROS, reactive oxygen species; IRP-IRE, iron regulatory protein-iron response element.