Background and Purpose Diabetic patients are at an increased risk of cardiovascular disease, in part due to inflammation and oxidative stress. These two pathological mechanisms also affect other organs and cells including the kidneys and progenitor cells. Angiotensin‐(1–7) [Ang‐(1–7)] has previously been shown to counterbalance pathological effects of angiotensin II, including inflammation and oxidative stress. The aim of this study was to investigate the effects of short‐term (2 weeks) Ang‐(1–7) treatment on cardiovascular and renal function in a mouse model of type 2 diabetes (db/db). Experimental Approach Eight‐ to nine‐week‐old db/db mice were administered either vehicle, Ang‐(1–7) alone, or Ang‐(1–7) combined with an inhibitor (losartan, PD123319, A‐779, L‐NAME or icatibant) daily for 14 days. Key Results An improvement in physiological heart function was observed in Ang‐(1–7)‐treated mice. Ang‐(1–7) also reduced cardiomyocyte hypertrophy, fibrosis and inflammatory cell infiltration of the heart tissue and increased blood vessel number. These changes were blocked by antagonists of the MAS1, AT2 and bradykinin receptors and inhibition of NO formation. Treatment with Ang‐(1–7) reduced glomerular damage and oxidative stress in kidney tissue. Bone marrow and circulating endothelial progenitors, as well as bone marrow mesenchymal stem cells, were increased in mice treated with Ang‐(1–7). Conclusions and Implications Short‐term Ang‐(1–7) treatment of young db/db mice improved heart function and reduced kidney damage. Treatment also improved bone marrow and circulating levels of endothelial and mesenchymal stem cells. All of this may contribute to improved cardiovascular and renal function.
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.
In the event of a nuclear disaster, the individuals proximal to the source of radiation will be exposed to combined radiation injury. As irradiation delays cutaneous repair, the purpose of this study was to elucidate the effect of combined radiation and burn injury (CRBI) on apoptosis and inflammation at the site of skin injury. Male C57Bl/6 mice were exposed to no injury, thermal injury only, radiation only (1 and 6 Gy) and CRBI (1 and 6 Gy) and euthanized at various times after for skin collection. TUNEL staining revealed that the CRBI 6 Gy group had a delayed and increased apoptotic response. This correlated with decreased recovery of live cells as compared to the other injuries. Similar response was observed when cleaved-caspase-3 immunohistochemical staining was compared between CRBI 6 Gy and thermal injury. TNFR1, caspase 8, Bax and IL-6 mRNA expression revealed that the higher CRBI group had delayed increase in mRNA expression as compared to thermal injury alone. RIPK1 mRNA expression and necrotic cell counts were delayed in the CRBI 6 Gy group to day 5. TNF-α and NFκB expression peaked in the CRBI 6 Gy group at day 1 and was much higher than the other injuries. Also, inflammatory cell counts in the CRBI 6 Gy group were lower at early time points as compared to thermal injury by itself. These data suggest that CRBI delays and exacerbates apoptosis and inflammation in skin as well as increases necrosis thus resulting in delayed wound healing.
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