Iron and ER stress in lupus nephritis

Lupus nephritis is a serious and common complication of systemic lupus erythematosus (SLE), and affects approximately 50% of SLE patients. Current treatments for lupus nephritis are only partially effective and have serious side effects, highlighting a need for new therapies.  Based on our novel findings of increased renal iron accumulation in a mouse model of SLE, and published evidence of iron metabolism proteins as biomarkers of lupus nephritis in humans, we propose increased renal iron accumulation as a novel mechanism of renal injury in SLE. Our preliminary data also show increased endoplasmic reticulum (ER) stress in the kidneys, providing an additional novel and possibly interrelated mechanism of injury. Using a mouse model of SLE, we will determine (1) the contribution of increased iron accumulation to renal injury in SLE; (2) the pathway(s) by which increased iron accumulation occurs; and (3) the contribution of ER stress to renal injury in SLE. In doing so, we will gain proof-of-concept data for reducing iron accumulation and ER stress as novel therapeutic strategies for lupus nephritis, and identify specific iron transport pathways to target. Agents that chelate iron and block ER stress are already FDA-approved, therefore our results have excellent translational potential.