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Page 12 of 18 Rodriguez. Plast Aesthet Res 2023;10:67 https://dx.doi.org/10.20517/2347-9264.2023.73

[28]
Figure 7. (From Liu ) Antagonism between HGF and TGF-β in the pathogenesis of renal fibrosis. (A) expression pattern of HGF and
TGF-β in the diseased kidney. The duration of injury may determine whether the damaged tissues undergo recovery or fibrogenesis.
Transient injury (dashed line) leads to a TGF-β/HGF ratio that favors HGF, resulting in tissue repair and regeneration, whereas chronic
injury dramatically changes the TGF-β/ HGF ratio to favor TGF-β, leading to tissue fibrosis; (B) function of TGF-β and HGF in fibrotic
kidneys. +: Promoting; -: suppressing; (C) therapeutic strategies for renal fibrosis. In the fibrotic kidney, the TGF-β/HGF ratio is out of
balance, and TGF- 1 signaling dominates. Thus, therapeutic strategies should include a reduction of TGF-β activity and/or
supplementation of HGF.

Constitutive fibrosis
TGF-β downregulates the production of collagenases and stimulates inhibitors of collagenases. The result is
an accumulation of a densely fibrotic matrix. HGF, on the contrary, downregulates inhibitors of
collagenases (TIMPS) and upregulates collagenases that break down matrix collagen. The net result is
collagen lysis and the release of other trophic factors bound in the matrix. This allows refashioning of the
matrix and facilitates cell migration.

EMT and EnMT
Both HGF and TGF-β stimulate endothelial and epithelial duct cells to migrate out of their vascular or
ductal structures into the interstitial matrix. However, in the case of TGF-β, the cells are driven to terminal
differentiation and change phenotype to mesenchymal fibroblast or myofibroblast, losing the ability to
replicate. They progress to senescence. By contrast, in the case of HGF, during migration, cells are
reprogrammed to the G phase, thus able to replicate or differentiate into other cell lineages. The cell lineage
0
is determined by other trophic factors, such as VEGF in the case of blood vessel formation. HGF also
stimulates cells to form tubular structures that can bud and ramify. This is key to organogenesis, vessel
formation, and duct formation. This is referred to as “morphogenesis”, and without it, appropriate organ
formation does not occur.

Angiogenesis
TGF-β degrades blood vessels by the twin mechanisms of EnMT and basement membrane degradation. It
depopulates their cellular components (endothelial cells) as well as structural components (basement
membranes). HGF also causes EnMT, but as mentioned before, cells are guided to form tubules, which are
precursors of blood vessels. Although HGF and VEGF are both important to blood vessel formation and
proliferation, HGF upregulates the production of VEGF and its receptor, and downregulates antiangiogenic
factors. Furthermore, knockout of VEGF in the presence of HGF does not impair vascularization, as HGF
[34]
stimulates vascularization via alternate mechanisms . In contrast, knockout of HGF does reduce
neovascularization significantly . Thus, HGF is also paramount in blood vessel formation.
[35]