Editorial: Advances in Mechanisms of Renal Fibrosis

Scarring of the glomerular and tubulointerstitial compartments is a hallmark of progressive kidney disease and is considered a common pathway leading to end-stage of renal failure. Renal fibrosis involves a complex interplay between intrinsic kidney cells, leukocytes, and fibroblasts in which transforming growth factor-β (TGF-β) plays a key role. Inhibition of TGF-β1 suppresses renal fibrosis in a number of animal models; however, TGF-β1 is also a negative regulator of the immune response so that targeting this key factor has been a difficult proposition. Much effort has focused on how TGF-β1 promotes renal fibrosis to identify other steps that can be targeted safely. The articles in this eBook describe advances in our understanding in the mechanisms of renal fibrosis that operate upstream and downstream of TGF-β/Smad signaling. TGF-β signals via canonical (Smad-based) and non-canonical (non-Smad based) pathways (Meng et al.). An important development is the demonstration that Smad2 and Smad3 exert opposing roles in renal fibrosis, with Smad2 being anti-fibrotic and Smad3 pro-fibrotic. This provides potential avenues for manipulating the Smad2/3 balance within Smad2/3/4 complexes to alter the outcome of TGF-β/Smad signaling. Two other proteins can suppress canonical TGFβ/Smad signaling. First, Smad7 has a negative feed-back role in TGF-β/Smad signaling. Genetic strategies to over-express Smad7 in mice inhibits renal fibrosis with the challenge being how to translate these proof of principle studies into the clinic (Meng et al.). Second, bone morphogenetic protein 7 (BMP7) is a member of the TGF-β super family which exerts anti-fibrotic effects in many models of renal fibrosis (Li et al.). This is attributed to counterbalancing the pro-fibrotic effects of TGF-β such as reducing collagen formation, increasingmatrix degradation and inactivatingmatrixproducing cells. However, the promise of recombinant BMP7 as an anti-fibrotic therapy has yet to be established in the clinic (Li et al.).