Blockade of Bradykinin receptors worsens the dystrophic phenotype of mdx mice: differential effects for B1 and B2 receptors

Abstract

The Kallikrein Kinin System (KKS) is a vasoactive peptide system with known functions in the maintenance of tissue homeostasis, renal function and blood pressure. The main effector peptide of KKS is Bradykinin (BK). This ligand has two receptors: a constitutive B2 receptor (B2R), which has been suggested to have anti-fibrotic effects in renal and cardiac models of fibrosis; and the inducible B1 receptor (B1R), whose expression is induced by damage and inflammation. Inflammation and fibrosis are hallmarks of Duchenne muscular dystrophy (DMD), therefore we hypothesized that the KKS may play a role in this disease. To evaluate this hypothesis we used the mdx mouse a model for DMD. We blocked the endogenous activity of the KKS by treating mdx mice with B2R antagonist (HOE-140) or B1R antagonist (DesArgLeuBK (DALBK)) for four weeks. Both antagonists increased damage, fibrosis, TGF-β and Smad-dependent signaling, CTGF/CCN-2 levels as well as the number of CD68 positive inflammatory cells. B2R blockade also reduced isolated muscle contraction force. These results indicate that the endogenous KKS has a protective role in the dystrophic muscle. The KKS may be a new target for future therapies to reduce inflammation and fibrosis in dystrophic muscle.

Proteomic identification of elevated saliva kallikrein levels in the mdx-4cv mouse model of Duchenne muscular dystrophy

“…At the level of pathophysiological mechanisms, elevated levels of circulating kallikrein isoform Klk-1 and Klk1-related peptidases suggest altered cellular signaling at the level of the kallikrein-kinin system and the regulation of tissue homeostasis [28] , as well as remodeling of the extracellular matrix and a modification of the immune response in X-linked muscular dystrophy [39] . Thus, comparative saliva proteomics is capable of establishing distinct changes in the biofluid protein complement and this study confirmed that liquid biopsy procedures are suitable bioanalytical tools for the systematic survey of complex pathobiochemical changes in muscular dystrophy [4] .…”

“…The kallikrein/kinin and bradykinin signaling axis of vasoactive peptides is involved in blood pressure regulation, tissue homeostasis and renal function. In addition, the endogenous kallikrein/kinin system was shown to be involved in various neurological diseases [27] and appears to play a protective role in dystrophic mdx muscle [28] . Building on these findings and the recent proteomic identification of greatly reduced levels of the kallikrein-1 related peptidase Klk1-b9 in mdx muscle [29] , it was of interest to study the status of kallikreins in mdx-4cv saliva specimens.…”

Role of Matricellular CCN Proteins in Skeletal Muscle: Focus on CCN2/CTGF and Its Regulation by Vasoactive Peptides

“…Nevertheless, the vasoactive peptides can also have local effects on several tissues [ 130 , 131 ]. In skeletal muscle, considerable evidence can be found in the literature showing that the pharmacological modulation of the renin-angiotensin system (RAS) and kallikrein kinin system (KKS) has beneficial effects on skeletal muscle in the context of different pathologies, including muscle atrophy, myopathies, muscular dystrophies, regeneration after trauma and sarcopenia, among others [ 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 ]. This section focuses on the RAS and KKS effects on skeletal muscle physiopathology that occur by the modulation of CCN proteins, with particular emphasis on the regulation of CCN2/CTGF and muscle fibrosis (summarized in Figure 3 ).…”

“…In skeletal muscle, both RAS and KKS are involved in modulating muscle mass. Furthermore, in muscle dystrophies, the classic RAS has detrimental effects, and the non-classical RAS axis and KKS seem to be protective [ 147 , 150 , 153 , 154 , 155 ].…”

“…Two known inhibitors were used, des-Arg-Leu-BK (DALBK) and HOE-140, to inhibit B1R and B2R, respectively. These treatments caused an increment in CCN2/CTGF levels, worsening fibrosis and inflammation compared to non-treated mdx mice [ 147 ]. These results suggest that endogenous KKS actively protects skeletal muscle from a more severe dystrophic phenotype, and that one of the mechanisms is the reduction of CCN2/CTGF.…”