Defining the Role of Integrin-linked Kinase in Ureteric Bud Growth and Branching During Murine Kidney Development

The mammalian kidney develops through two major processes: nephrogenesis and renal branching morphogenesis. During branching morphogenesis, precise regulation of growth factor signaling is important for branching, elongation, and differentiation of the developing ureteric bud (UB). Defects in renal branching morphogenesis can lead to the development of kidneys incapable of supporting postnatal life. Despite their critical role in renal branching, the intracellular signaling pathways mediating the response to growth factor signaling in the developing kidney are poorly understood. Herein, I describe the crucial role of an intracellular scaffold protein, Integrin-linked Kinase (ILK), in kidney development. ILK is expressed within the developing UB and the conditional deletion of Ilk from this cell lineage during murine kidney development leads to postnatal renal hypoplasia or hypodysplasia. Characterization of the phenotype of Ilk-deficient kidneys demonstrated a role for Ilk in embryonic renal branching in vivo. At a mechanistic level, whole transcriptome analysis identified downstream gene targets of Ilk-dependent signaling involved in epithelial tube development that are mis-regulated in the absence of Ilk. The downregulated genes that were expressed in the developing UB included: i) known regulators of renal branching (Wnt11, Sox8, CXCR4), and ii) genes with unknown function in the developing kidney (Krt23, Slco4c1, Myb). Furthermore, activation of p38MAPK signaling was decreased in Ilk-deficient kidneys and a subset of Ilk-dependent genes requires p38MAPK activation for their expression in vitro. Loss of Ilk also results in misregulation of MAPK phosphatase activity in embryonic kidneys, with an upregulation of the Dual Specificity Phosphatase 8 (DUSP8). DUSP8 overexpression attenuates the activation of p38MAPK and decreases expression of Wnt11 and Krt23 in vitro. In sum, the combined approach of phenotypic, molecular, and genomic analysis of the role of ILK provided a comprehensive understanding of the role of this important protein in the developing kidney. This research improves our understanding of the regulation of intracellular signaling pathways during kidney development and provides knowledge that can be applied to the understanding and treatment of human renal disease.Ph