TGF-β promotes fibrosis after severe acute kidney injury by enhancing renal macrophage infiltration

Transforming growth factor–β in tissue fibrosis

“…Disruption of pathways involved in macrophage recruitment reduced TGF-β synthesis and attenuated fibrosis in models of acute and chronic fibrotic injury (Dewald et al, 2005;Frangogiannis et al, 2007;Young et al, 2016), suggesting that macrophages are a major source of TGF-β (Juban et al, 2018). In contrast, in models of ischemic and obstructive renal injury, myeloid cell-specific deletion of TGF-β1 did not affect kidney fibrosis (Huen et al, 2013), as other cell types (such as epithelial cells) appeared to serve as a major source of TGF-βs (Chung et al, 2018). Platelets (Meyer et al, 2012), T cell subsets (Celada et al, 2018;Lo Re et al, 2011;Wang et al, 2007), fibroblasts (Nevers et al, 2017), and mast cells (Gordon and Galli, 1994) have also been suggested to represent important sources of TGF-β in various pathophysiological models of tissue fibrosis.…”

Mitophagy-dependent macrophage reprogramming protects against kidney fibrosis

“…TGF-β1, a pluripotent multifunctional and a key profibrogenic cytokine, favors the transdifferentiation of M2 macrophages into myofibroblasts (7,8). Monocyte/ macrophage-specific deletion of TGF-β receptor II has been shown to significantly reduce the infiltration of macrophages and tubulointerstitial fibrosis (9). However, macrophage-specific TGF-β1 deletion failed to prevent kidney fibrosis (10,11).…”

Potential targeted therapy and diagnosis based on novel insight into growth factors, receptors, and downstream effectors in acute kidney injury and acute kidney injury-chronic kidney disease progression

“…106 It is noteworthy that TGF-β/Smads play a predominant role in the progression of AKI to CKD. 118 In the tubular injury phase, proximal tubular cells dedifferentiate and proliferate to replace lost epithelial cells. However, when the insult is severe and unresolvable, some cells fail to redifferentiate and continue to produce growth factors such as TGF-β, finally leading to renal fibrosis.…”

“…119 Additionally, a recent study showed that TGF-βRII deletion in macrophages prevents tubulointerstitial fibrosis following severe ischemic renal injury by abrogating TGFβ-dependent chemoattraction of macrophages. 118 Collectively, the functions of TGF-β/Smads may vary according to their activation level, disease stages, and types of AKI models, which need to be further validated. Exploring the detailed function of TGF-β and downstream Smads may help us to better understand the pathological mechanisms of AKI and its progression to CKD.…”