The role of cell plasticity in progression and reversal of renal fibrosis

Abstract

The need for novel insights into the mechanisms of progression of renal disease has become urgent during the last several years because of the increasing incidence of chronic renal disease worldwide. Independent of the underlying disease, the subsequent progression of renal fibrosis is characterized mainly by both an exaggerated synthesis and abnormal accumulation of extracellular matrix proteins produced by mesenchymal cells within the kidney. These cells are mainly myofibroblasts deriving from a variety of renal cells such as vascular smooth muscle, mesangial, resident stem, tubular epithelial, vascular endothelial cells or pericytes. The appearance of myofibroblasts is a reversible process, as suggested by studies in experimental models showing regression of renal fibrosis during therapy with antagonists and/or blockers of the renin-angiotensin system. An additional factor that can also affect the mechanisms of progression/regression of fibrosis is the plasticity of podocytes controlling glomerular filtration.

Figure 1

Angiotensin II can induce simultaneously a variety of effects on cells such as contractility, inflammation, differentiation, proliferation, apoptosis or extracellular matrix gene activation, which are capable of interacting with each other, and according to the specific environmental, hormonal or homoeostatic conditions within the kidney can lead (or not) to the development of fibrosis.

Figure 2

The complexity of the roles of different members of the TGFbeta/bone morphogenetic proteins (BMP) superfamily in the development of renal fibrosis. Latent TGFbeta binding protein-4 (LTBP-4) and connective tissue growth factor (CTGF) act as cofactors of TGFbeta leading to the activation of TGF receptors, the stimulation of SMAD2 and SMAD3, and the formation of the SMAD 2/3/4 complex. This complex inhibits the transcription factor Id-1 and promotes the induction of mesenchymal phenotype. In contrast, BMPs antagonize the effect of TGFbeta by stimulating SMADs 1/5/8, which capture SMAD4, inhibit the formation of the SMAD 2/3/4 complex and induce the epithelial phenotype. New players in this interaction are the endogenous inhibitors of BMPs, noggin, uterine sensitization–associated gene-1 (USAG-1) and gremlin which block the interaction of BMPs with their receptors and inactivate the SMAD 1/5/8 cascade. As result, SMAD4 is free to interact with SMAD2 and SMAD3, and thus, the final outcome is a shift towards the pro-fibrotic action of TGFbeta.

Figure 3

Cellular mechanisms involved in the phenotype changes during progression or regression of renal fibrosis. Pro-fibrotic agents (such as angiotensin II, endothelin or TGFbeta) modify the renal morphology and function by shifting the gene expression of proteins towards a fibrotic state in all renal compartments. Data from a variety of experimental models show that renal fibrosis is reversible and that is possible to retrieve a normal phenotype following therapy with the agents listed in the lower part of the figure.