Effects of combined radiation and burn injury on the renin–angiotensin system

Abstract

The renin angiotensin system (RAS) plays an important role in wound repair; however, little is known pertaining to RAS expression in response to thermal and the combination of radiation plus burn injury (CRBI). The purpose of this study was to test the hypothesis that thermal injury modifies expression of RAS components and CRBI delayed this up-regulation of RAS. Skin from uninjured mice was compared to mice receiving local thermal injury or CRBI (injury site). Skin was analyzed for gene and protein expression of RAS components. There was an initial increase in the expression of various components of RAS following thermal injury. However, in the higher CRBI group there is an initial decrease in AT1b (vasoconstriction, pro-proliferative) AT2 (vasodilation, differentiation) and Mas (vasodilation, anti-inflammatory) gene expression. This corresponded with a delay and decrease in AT1, AT2 and MAS protein expression in fibroblasts and keratinocytes. The reduction in RAS receptor positive fibroblasts and keratinocytes correlated with a reduction in collagen deposition and keratinocyte infiltration into the wounded area resulting in a delay of re-epithelialization following CRBI. These data support the hypothesis that delayed wound healing observed in subjects following radiation exposure may be in part due to decreased expression of RAS.

Angiotensin II stimulates canonical TGF-β signaling pathway through angiotensin type 1 receptor to induce granulation tissue contraction

“…Of the two widely studied AngII receptors, AT1-receptor is characterized as the primary regulator for AngII mediated dermal fibrosis. In one study on the effects of thermal skin injury on the Renin-Angiotensin-System in a murine model, the data indicated that AT1-receptor expression was increased in the fibroblasts of injured mice but absent in the fibroblasts of unwounded skin [23]. Similarly, AT1-receptor, as compared to AT2-receptor, was found to be more prominently expressed in the dermis of wounded rats [24].…”

Accelerated healing of diabetic wounds by NorLeu3-angiotensin (1-7)

“…With injury, expression of the receptor for NorLeu 3 -A(1-7), Mas, increases in skin. The cellular components with upregulated expression include cells of the hair follicle, hyperplastic epidermis and dermis [18]. Unpublished studies using microarray technology show that a cassette of genes is upregulated in granulation tissue of wounds treated with NorLeu 3 -A(1-7) (compare first lane from the right [G-P; granulation-placebo] with the fourth lane from the right [G-N; granulation-NorLeu 3 -A(1-7)].…”

“…In human skin, AT 1 and AT 2 receptors were found in the epidermis and in dermal vessel walls [8]. Recently, an upregulation of the Mas receptor, the functional receptor for A(1-7), in the skin after injury has been shown [18] (Figure 2). The same expression pattern was found for angiotensinogen, the parent protein, renin and angiotensin converting enzyme (ACE).…”

NorLeu3-Angiotensin (1-7) [DSC127] as a Therapy for the Healing of Diabetic Foot Ulcers

“…15 Recently, an upregulation of the Mas receptor, the functional receptor for A(1-7), in the skin after injury has been shown. 25 Once the activity of A(1-7) was identified, a series of analogs were generated and tested for activity in both in vitro and in vivo models of healing. In these studies, NorLeu3-A(1-7) was found to be most active in the acceleration of wound repair and had the novel mechanism of restoration of skin architecture, for example, regeneration.…”