Exploring unconventional targets in myofibroblast transdifferentiation outside classical TGF- β signaling in renal fibrosis

Abstract

We propose that the key initiators of renal fibrosis are myofibroblasts which originate from four predominant sources-fibroblasts, pericytes, endothelial cells and macrophages. Increased accumulation of renal interstitial myofibroblasts correlates with an increase in collagen, fibrillar proteins, and fibrosis severity. The canonical TGF-$\beta$ pathway, signaling via Smad proteins, is the central molecular hub that initiates these cellular transformations. However, directly targeting these classical pathway molecules has proven challenging due their integral roles in metabolic process, and/or non-sustainable effects involving compensatory cross-talk with TGF-β. This review explores recently discovered alternative molecular targets that drive transdifferentiation into myofibroblasts. Discovering targets outside of the classical TGF-β/Smad pathway is crucial for advancing antifibrotic therapies, and strategically targeting the development of myofibroblasts offers a promising approach to control excessive extracellular matrix deposition and impede fibrosis progression.

Keywords: TGF-beta; extracellular matrix; fibroblast transition; fibrosis; kidney; myofibroblasts; renal fibrosis; transdifferentiation.

FIGURE 1

Exploring unconventional targets in myofibroblast transdifferentiation outside classical TGF- $\mathrm{\beta }$ signaling in renal fibrosis. (A) Illustration representing classical tubulointerstitial kidney fibrosis steps. DAMPs: Damage-associated molecular patterns, PAMPs: Pathogen-associated molecular pattern molecules, IFNγ: Interferon gamma. A portion of the figure utilizes adapted images from Servier Medical Art, licensed under Creative Commons Attribution 4.0 Unported License. (B). Summary of emerging targets that cross-talk with TGF- $\mathrm{\beta }$ outside of the canonical TGF- $\mathrm{\beta }$ /Smad signaling cascade. Alternative molecular targets illustrated drive transdifferentiation into myofibroblasts from origin cells: (1) fibroblasts, (2) pericytes, (3) endothelial cells and (4) macrophages. Double arrow signifies prolonged and increased signaling. Red X indicates when removal of a potential target drives cellular transformation. TGF- $\mathrm{\beta }$ : Transforming growth factor-beta, TRPC6: transient receptor potential cation channel subfamily C member 6, Smads: Suppressor of Mothers against Decapentaplegic, MST1/2: mammalian STE20-like protein kinase 1/2, YAP: Yes-associated protein, TAZ: transcriptional coactivator with PDZ-binding motif, miR-21-5p: microRNA-21-5p, P38: p38 Mitogen-Activated Protein Kinase, VDR: vitamin D receptor, miR-132: microRNA-132, DCN: decorin, ZEB2: Zinc finger E-box binding homeobox 2, STAT3: Signal Transducer and Activator of Transcription 3, ERK: Extracellular Signal-Regulated Kinase, MMP-9 - Matrix Metalloproteinase 9, miR-126-3p: microRNA-126,-3p WNT: Wingless-related integration site, A2B: Adenosine A2B Receptor, MR: aldosterone mineralocorticoid receptor, CXCL10: C-X-C motif chemokine ligand 10, Pou4f1: POU Class 4 Homeobox 1, TCF: T-Cell Factor.