Our overall goal is to define how cell-extracellular matrix interactions regulate kidney homeostasis in health and disease. These interactions are studied from animals to molecules using transgenic mouse models, cell biological and biochemical assays. We previously defined the contribution of laminin (LM) receptor integrins, integrin ?3?1 and ?6 containing integrins, to ureteric bud (UB) development. Recently, we made an unexpected novel observation that LM receptors regulate tubular epithelial cell inflammation and kidney tubulointerstitial fibrosis in aged and injured mice. These new findings form the basis of this renewal. Integrins are transmembrane receptors composed of ? and ? subunits that mediate interactions between cells and ECM. There are 18 ? and 8 ? subunits, which form dimers with different ligand binding properties. Integrins are classified into collagen, LM and RGD binding receptors and the principal LM binding integrins are ?3?1, ?6?1 and ?6?4. Ligand specificity is defined by the extracellular domain while the transmembrane domain (TM) and the cytoplasmic tail mediate specialized functional intracellular signaling. In the last grant cycle, we showed that deleting the integrin (Itg) ?3 subunit in the UB causes minor morphological developmental abnormalities, while deleting the Itg?6 subunit did not alter development. Mice lacking Itg?3 in the UB are highly susceptible to kidney fibrosis after unilateral ureteric obstruction (UUO), while the integrin Itg?6-null mice develop severe tubular dilatation and cellular apoptosis, but no fibrosis. Mice lacking all LM binding integrins in the UB (Itg?3/?6- null) have the same developmental phenotype as the Itg?3-null mice, but with age they develop severe tubulointerstitial fibrosis and inflammation. These mice are also susceptible to severe inflammation, fibrosis and tubular apoptosis after UUO and chronic proximal tubule injury. Utilizing collecting duct cells from these mice, we show that in addition to their classical adhesion functions, the LM binding integrins regulate epithelial cell apoptosis, inflammation and collagen production. Excess collagen synthesis occurs when Itg?3 is deleted, apoptosis when ?6 is deleted and, in addition to these processes, inflammation occurs in Itg?3/?6-null mice. In this proposal, we will investigate the mechanisms whereby the LM-binding receptors regulate renal tubular epithelial cell responses to aging and injury. We will test the hypothesis that loss of kidney tubule epithelial cell signaling from LMs, via ?3?1 an ?6-containing integrins, causes accelerated inflammation and excessive fibrosis and apoptosis resulting in chronic kidney disease in the following aims: 1) Define the mechanisms whereby loss of LM binding integrin signaling predisposes kidney tubules to chronic kidney injury. 2) Determine the mechanisms whereby the loss of LM binding integrin signaling promotes renal tubular epithelial cell apoptosis, inflammation and collagen production.
We anticipate that this study will generate novel insights into the mechanisms whereby the laminin binding integrins protect the kidney tubules from injury and fibrosis. This knowledge is fundamental to our understanding of how the renal tubules function in health and disease.
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