The nmf240 phenotype closely resembles that reported for Clcn2 knockout mice. The observation that heterozygous nmf240 mice present with a reduced ERG light peak component suggests that CLCN2 is necessary for the generation of this response component.

Integrin ␣1␤1 negatively regulates the generation of profibrotic reactive oxygen species (ROS) by inhibiting epidermal growth factor receptor (EGFR) activation; however, the mechanism by which it does this is unknown. In this study, we show that caveolin-1 (Cav-1), a scaffolding protein that binds integrins and controls growth factor receptor signaling, participates in integrin ␣1␤1-mediated EGFR activation. Integrin ␣1-null mesangial cells (MCs) have reduced Cav-1 levels, and reexpression of the integrin ␣1 subunit increases Cav-1 levels, decreases EGFR activation, and reduces ROS production. Downregulation of Cav-1 in wild-type MCs increases EGFR phosphorylation and ROS synthesis, while overexpression of Cav-1 in the integrin ␣1-null MCs decreases EGFR-mediated ROS production. We further show that integrin ␣1-null MCs have increased levels of activated extracellular signal-regulated kinase (ERK), which leads to reduced activation of peroxisome proliferator-activated receptor ␥ (PPAR␥), a transcription factor that positively regulates Cav-1 expression. Moreover, activation of PPAR␥ or inhibition of ERK increases Cav-1 levels in the integrin ␣1-null MCs. Finally, we show that glomeruli of integrin ␣1-null mice have reduced levels of Cav-1 and activated PPAR␥ but increased levels of phosphorylated EGFR both at baseline and following injury. Thus, integrin ␣1␤1 negatively regulates EGFR activation by positively controlling Cav-1 levels, and the ERK/PPAR␥ axis plays a key role in regulating integrin ␣1␤1-dependent Cav-1 expression and consequent EGFR-mediated ROS production.Integrins are transmembrane receptors for extracellular matrix components and are composed of noncovalently bound ␣ and ␤ subunits. In mammals, 1 of 18 ␣ subunits heterodimerizes with 1 of 8 ␤ subunits to form 24 distinct integrins, each with specific but overlapping functions (4, 29). Integrins regulate cellular processes such as cell adhesion, differentiation (2), cell cycle progression (26), reactive oxygen species (ROS) production (10, 72), and extracellular matrix synthesis and remodeling (23). In addition, integrins interact with and regulate the activity of different growth factor receptors (3), and this cross talk coordinates biological processes by regulating downstream signaling pathways (8,55,58,61). Integrin occupancy causes growth factor receptor autophosphorylation (44), and growth factor receptors and integrins associate following growth factor stimulation or integrin activation (5, 61, 73).Caveolin-1 (Cav-1) is one of the three members of the caveolin family and is a structural protein involved in the formation of caveola-rich membrane domains (64). Caveolae are clearly defined, small, flask-shaped invaginations of the plasma membrane enriched in sphingolipids and cholesterol and are implicated in transcytosis, lipid metabolism, and receptor trafficking (35). Changes in plasma membrane localization and/or expression of Cav-1 can profoundly affect Cav-1-mediated functions. Different factors can regulate Cav-1 expression at both tr...