lntegrin binding proteins and the kidney

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A hallmark of chronic kidney disease (CKD) is advancing tubulointerstitial (TI) fibrosis. While new mechanisms of fibrosis have been uncovered in recent decades, effective treatment to directly halt or reverse this process remains elusive. Our group has a long-standing interest in defining how extracellular matrix (ECM) receptors such as integrins and their binding partners regulate kidney development and response to injury. Among the integrin binding partners, we focus on the integrin linked kinase (ILK); pinch; α-parvin complex of scaffold proteins, also known as the IPP complex. We recently uncovered a novel modality to interfere with integrin dependent signaling pathways mediated by the IPP complex that may represent a new strategy to treat and prevent TI fibrosis and ultimately CKD. Integrins are transmembrane receptors composed of non-covalently bound α and β subunits. β1 is the most abundantly expressed subunit in the kidney and can bind 12 different α subunits. The β1 cytoplasmic tail functions by binding multiple cytoplasmic proteins which regulate integrin-mediated signaling and cytoskeleton modulation. The IPP complex is a major scaffolding hub that binds the integrin β1 cytoplasmic tail and its key function is to bundle actin filaments, thereby transmitting mechanical signals between integrins and the actin cytoskeleton. A normal actin cytoskeleton is required for most cell functions necessary for embryonic development and recovery of tissue from injury. ILK is the major scaffold protein that brings the IPP complex together; however, the α and β parvins are the major IPP complex proteins that regulate the actin cytoskeleton. We have preliminary evidence that α-parvin is required for normal kidney development and repair after injury. Deletion of α-parvin in mice at the initiation of the kidney collecting system (E10.5) causes severely dysmorphic kidneys with excessive basolateral F-actin. We also provide evidence that deleting α-parvin in the fully developed kidney collecting system (E 18.5) results in excessive tubular injury following a unilateral ureteric obstruction (UUO) model. Mice carrying a mutant ILK unable to bind to α-parvin (K-to-M mutation in a.a. 220: ILK-K220M mice) in the developing collecting system develop normally and wild-type mice treated with the small molecule Csbl-1 (that interferes with the ILK-α-parvin interaction) have decreased renal fibrosis following UUO. These data strongly suggest that α-parvin performs multiple cellular functions that are independent of its interactions with ILK and paradoxically disrupting ILK binding to α-parvin improves the response of the kidney to injury. Finally, we have evidence that α-parvin-null collecting duct (CD) cells have excessive F-actin formation, increased cell adhesion, spreading and migration as well as a profound increase in activated RhoA and Cdc42. Based on these data, we hypothesize that α-parvin-mediated regulation of actin dynamics via Rho-GTPase signaling promotes kidney tubule development, homeostasis, and recovery from injury. This hypothesis will be tested in the following 2 aims. Aim 1. Determine the role of α-parvin in kidney tubule development and injury. We will test the hypothesis that α-parvin-mediated actin filament bundling is required for normal kidney tubule development and protection from injury. Aim 2. Determine the mechanisms whereby α-parvin regulates actin-bundling dependent epithelial cell function. We will test the hypothesis that α-parvin-mediated inhibition of RhoA and Cdc42 activity promotes cofilin-mediated actin turnover dependent epithelial cell polarity and proliferation that is required for normal tubule formation and repair.