2.2.11. Fibrosis

Renal fibrosis is the end result of nearly all progressive renal diseases. Fibrosis is a maladaptive repair process associated with chronic inflammation. It is characterized by progressive remodeling and destruction of renal tissue in an attempt to replace injured cells. Although the initial stages of this repair process may be beneficial, prolonged activation of growth factors and cytokines leads to the replacement of normal renal parenchyma with collagen and other connective tissue fibers [97].

It is generally accepted that fibroblasts and myofibroblasts are key cells involved in renal fibrosis. Under normal conditions, fibroblasts synthesize many of the constituents of the extracellular matrix. It is well accepted that myofibroblasts are activated fibroblasts. Renal injury leads to numerous stimuli that may cause transformation of fibroblasts to myofibroblasts. These stimuli include the production of inflammatory cytokines (e.g., TGFβ, platelet-derived growth factor (PDGF), fibroblast growth factor 2 (FGF-2)), hypoxia, and cell contact with leukocytes and macrophages. Interestingly, renal fibroblasts maintain their activated phenotype in a setting of fibrosis even if the initial cause is no longer present [98].

Published evidence suggests that renal epithelial cells play an important role in renal fibrosis due to epithelial-to-mesenchymal transition [98–100]. This transition appears to be induced by interleukin-like epithelial mesenchymal transition inducer (ILEI) in response to TGF-β1 through Akt (protein kinase B) and ERK (extracellular signal-regulated kinase) pathways [101]. Following this transition, renal tubular epithelial cells lose their normal morphology, tight junctions, and epithelial cell markers (e.g., E-cadherin), and begin expressing mesenchymal markers such as α-smooth muscle actin (α-SMA) and vimentin. These alterations facilitate the progression of renal interstitial fibrosis and CKD [101].

PDGFs play an important role in the processes that lead to renal fibrosis [102]. PDGF receptor-β (PDGFR- β) is a tyrosine-kinase receptor for PDGF-B and PDGF-D. Upon activation, PDGFR-β induces downstream signaling that triggers cell proliferation, migration, and differentiation, leading to extracellular matrix deposition. There is experimental evidence that PDGFR-β activation alone is sufficient to induce progressive renal fibrosis and renal failure, key aspects of CKD [103]. PDGFR-β is a potential target for therapeutic intervention to slow the progression of kidney disease.
