Ferroptosis Promotes Cyst Growth in Autosomal Dominant Polycystic Kidney Disease Mouse Models.

Abstract

Autosomal dominant polycystic kidney disease (ADPKD), the most common inherited kidney disease, is regulated by different forms of cell death, including apoptosis and autophagy. However, the role in ADPKD of ferroptosis, a recently discovered form of cell death mediated by iron and lipid metabolism, remains elusive. To determine a pathophysiologic role of ferroptosis in ADPKD, we investigated whether the absence of <i>Pkd1</i> (encoding polycystin-1) affected the expression of key factors involved in the process of ferroptosis, using Western blot and qRT-PCR analysis in <i>Pkd1</i> mutant renal cells and tissues. We also examined whether treatment with erastin, a ferroptosis inducer, and ferrostain-1, a ferroptosis inhibitor, affected cyst growth in <i>Pkd1</i> mutant mouse models. We found that kidney cells and tissues lacking <i>Pkd1</i> exhibit extensive metabolic abnormalities, including reduced expression of the system Xc^- amino acid antiporter (critical for import of cystine), of iron exporter (ferroportin), and of GPX4 (a key and negative regulator of ferroptosis). The abnormalities also include increased expression of iron importers (TfR1, DMT1) and HO-1, which in turn result in high iron levels, low GSH and GPX4 activity, increased lipid peroxidation, and propensity to ferroptosis. We further found that erastin increased, and ferrostatin-1 inhibited ferroptotic cell death and proliferation of <i>Pkd1</i>-deficient cells in kidneys from <i>Pkd1</i> mutant mice. A lipid peroxidation product increased in <i>Pkd1</i>-deficient cells, 4HNE, promoted the proliferation of survived <i>Pkd1</i> mutant cells <i>via</i> activation of Akt, S6, Stat3, and Rb during the ferroptotic process, contributing to cyst growth. These findings indicate that ferroptosis contributes to ADPKD progression and management of ferroptosis may be a novel strategy for ADPKD treatment.