The laminin-binding integrins regulate nuclear factor kappa-β-dependent epithelial cell polarity and inflammation

The main laminin (LM)-binding integrins α3β1, α6β1 and α6β4 are co-expressed in the developing kidney collecting duct (CD) system. We previously showed that deleting the integrin α3 or α6 subunit in the ureteric bud (UB), which gives rise to the kidney collecting system, caused either a mild or no branching morphogenesis phenotype, respectively. To determine whether these two integrin subunits co-operate in kidney CD development, we deleted α3 and α6 in the developing UB. The collecting system of the double knockout phenocopied the α3 integrin conditional knockout. However, with age the mice developed severe inflammation and fibrosis around the CDs resulting in kidney failure. Integrin α3α6 null CD epithelial cells showed increased secretion of pro-inflammatory cytokines and displayed mesenchymal characterisitcs causing loss of barrier function. These features resulted from increased NF-κB activity, which regulated the Snail/Slug transcription factors and their downstream targets. These data suggest that LM-binding integrins play a key role in the maintenance of kidney tubule epithelial cell polarity and decrease pro-inflammatory cytokine secretion by regulating NF-κB-dependent signaling.