Role of fibroblast activation in inducing interstitial fibrosis.
Tubulointerstitial fibrosis is an obligate finding in end-stage diseased kidneys. Renal fibrosis is defined as excessive matrix deposition that leads to tissue destruction and impairment of renal function. This process is often independent of the initial underlying disease and is not self-limited, in contrast to normal wound healing. Fibroblasts are the main effector cells in fibrogenesis, and mainly contribute to increased synthesis of matrix components. Increased matrix production is preceeded by massive proliferation of fibroblasts. The transformation from quiescent interstitial cells to proliferating and excessively matrix-producing cells has been termed fibroblast activation, which includes functional implications as well as phenotypic changes such as the expression of alpha-smooth muscle actin ("myofibroblasts"). Activation of fibroblasts typically occurs through four distinct mechanisms: stimulation by growth factors ("auto- and paracrine"), by direct cell-cell contacts, by extracellular matrix via integrins, and by environmental conditions such as hyperglycemia or hypoxia in renal disease. The crucial step though, that distinguishes wound healing from fibrosis, is the perpetuation of the activated state. The clarification of cellular events connected with fibrogenesis has led to new approaches for therapy. Direct targeting of fibroblasts, inhibition of matrix deposition and specific inhibition of fibroblast activation have proved successful in experimental models and thus may lead to new approaches in the treatment of progressive renal disease.
Zeisberg
M
M
Center for Internal Medicine, Nephrology & Rheumatology, Georg-August University, Göttingen, Germany.
Strutz
F
F
Müller
G A
GA
D000818:Animals; D005347:Fibroblasts / Q000502:physiology*; D005355:Fibrosis; D006801:Humans; D007668:Kidney / Q000473:pathology* / Q000503:physiopathology*; D007676:Kidney Failure, Chronic / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*; D009130:Muscle, Smooth / Q000473:pathology / Q000503:physiopathology