The Role of the Renin-Angiotensin System and Vitamin D in Keloid Disorder—A Review

Abstract

Keloid disorder (KD) is a fibroproliferative condition characterized by excessive dermal collagen deposition in response to wounding and/or inflammation of the skin. Despite intensive research, treatment for KD remains empirical and unsatisfactory. Activation of the renin-angiotensin system (RAS) leads to fibrosis in various organs through its direct effect and the resultant hypertension, and activation of the immune system. The observation of an increased incidence of KD in dark-skinned individuals who are predisposed to vitamin D deficiency (VDD) and hypertension, and the association of KD with hypertension and VDD, all of which are associated with an elevated activity of the RAS, provides clues to the pathogenesis of KD. There is increasing evidence implicating embryonic-like stem (ESC) cells that express ESC markers within keloid-associated lymphoid tissues (KALTs) in keloid lesions. These primitive cells express components of the RAS, cathepsins B, D, and G that constitute bypass loops of the RAS, and vitamin D receptor (VDR). This suggests that the RAS directly, and through signaling pathways that converge on the RAS, including VDR-mediated mechanisms and the immune system, may play a critical role in regulating the primitive population within the KALTs. This review discusses the role of the RAS, its relationship with hypertension, vitamin D, VDR, VDD, and the immune system that provide a microenvironmental niche in regulating the ESC-like cells within the KALTs. These ESC-like cells may be a novel therapeutic target for the treatment of this enigmatic and challenging condition, by modulating the RAS using inhibitors of the RAS and its bypass loops and convergent signaling pathways.

Acne keloidalis nuchae and hypertension in black subjects: a case–control study

“…In addition, activation of the renin-angiotensin system is known to cause angiotensin II-induced arterial vasoconstriction resulting in elevated blood pressure. Similarly, the association between the renin-angiotensin system and tissue fibrosis is well documented [14,15]. The mechanism highlighting the association between renin-angiotensin system activity and fibrosis is thought to be an increased expression of growth factor (TGF-1) caused by angiotensin II, which plays a central role in fibrogenesis [16].…”

Therapeutic Strategies by Regulating Interleukin Family to Suppress Inflammation in Hypertrophic Scar and Keloid

“…Initial results with angiotensin receptor blocker (ARB) and angiotensin converting enzyme inhibitor (ACEI) in the treatment of keloid and HS were encouraging ( Kilmister et al, 2019 ). Renin angiotensin aldosterone system (RAS) components which are expressed in various cells of skin and act independently of plasma RAS, play an important role in wound healing and scar formation.…”

The role of the renin‐angiotensin system in skin physiology and pathophysiology

“…[42] There is evidence that an overactivated cutaneous RAS is involved in this process, because Ang II via the AT 1 R is known to act pro-fibrotic [8,43] and because levels of Ang II and expression of AT 1 Rs and the enzymes catalysing Ang II formation, ACE and chymase, are increased in hypertrophic scars and keloids from rodents and humans. [44][45][46][47] As in other fibrotic conditions, pro-fibrotic signalling of the AT 1 R in hypertrophic scars or keloids involves activation of canonical and non-canonical TGFβ signalling thus leading to increased ECM production, myofibroblast transition and granulation tissue contraction. [35,37,43] Consequently, a multitude of studies has tested inhibition of the Ang II-AT 1 R axis by ACE inhibitors and AT 1 R antagonists for the prevention or treatment of hypertrophic scars and keloids in preclinical models.…”