Signaling Crosstalk between Tubular Epithelial Cells and Interstitial Fibroblasts after Kidney Injury.

BACKGROUND A wide variety of kidney diseases ultimately lead to tubulointerstitial damage. The initial site of injury is usually the renal tubules, with activation of fibroblasts occurring later. Self-limited disease is characterized by transient cellular activation with timed deactivation and ultimately a return to normal functioning, whereas sustained responses characterize chronic disease and the development of irreversible fibrosis. The underlying molecular and cellular mechanisms of this cascade of events remain an area of active research. Current data overwhelmingly support a role for crosstalk between the tubular epithelium and the interstitial fibroblast that mediates both repair/regeneration and progressive disease. This epithelial-mesenchymal communication (EMC) is regulated by a variety of soluble ligands binding to cell surface receptors to induce intracellular signaling events. SUMMARY EMC is an important mechanism whereby tubular epithelium and fibroblasts/mesenchymal cells crosstalk to affect renal physiology and pathology. Numerous soluble factors such as sonic hedgehog, Wnt ligands, transforming growth factor-β, hepatocyte growth factor, connective tissue growth factor, and angiotensin II all participate in bidirectional EMC. Recent studies have also identified exosomes as a vehicle to mediate EMC during kidney injury. In general, while the short-term activity of EMC factors is renoprotective, prolonged activation of these factors leads to chronic disease and fibrosis. KEY MESSAGES The discovery of a complex and intricate system of communication between tubular cells and fibroblasts is a new paradigm in our understanding of renal fibrosis. An appreciation of both their regenerative and pathologic functions will inform the development and use of targeted therapeutic interventions.