Progression of chronic kidney disease: too much cellular talk causes damage

Abstract

Tubulointerstitial fibrosis, tubular atrophy, and peritubular capillary rarefaction are major hallmarks of chronic kidney disease. The tubulointerstitium consists of multiple cell components including tubular epithelial, mesenchymal (fibroblasts and pericytes), endothelial, and inflammatory cells. Crosstalk among these cell components is a key component in the pathogenesis of this complex disease. After severe or recurrent injury, the renal tubular epithelial cells undergo changes in structure and cell cycle that are accompanied by altered expression and production of cytokines. These cytokines contribute to the initiation of the fibrotic response by favoring activation of fibroblasts, recruitment of inflammatory cells, and loss of endothelial cells. This review focuses on how augmented growth factor and cytokine production induces epithelial crosstalk with cells in the interstitium to promote progressive tubulointerstitial fibrosis after renal injury.

Keywords: endothelial cells; epithelial cells; fibroblasts; fibrosis; inflammation; interstitium.

Figure 1. Schematic representation of crosstalk among kidney tubular epithelial cells, fibroblasts, endothelial cells and inflammatory cells that could lead to the progression of chronic kidney disease

Injured epithelial cells produce HIF-1α that promotes epithelial cell dedifferentiation as well as VEGF production. This growth factor, in turn, promotes macrophage recruitment to the site of injury and stimulates endothelial cell proliferation leading to leaky vessels. Injured epithelial cells can also produce other growth factors such as CSF-1, a potent chemoattractant for monocytes that can then differentiatite into dendritic cells or macrophages. Injured epthelial cells can also produce PDGF and TGF-β which promote fibroblast proliferation and fibroblast to myofibroblast differentiation. Finally, fibroblasts can produce thrombospondin-1 that, in addition to activating TGF-β, inhibits endothelial cell proliferation contributing to capillary rarefaction.