Cardio-renal axis regulation in the deep-diving hooded seal
1 Formål
Cardiovascular disease is still the leading cause of premature death in the western world. The kidney is one of the first organs to disfunction in fatal cardiac arrest, the main problem being inadequate perfusion and resulting ischemia. The resulting cardiorenal syndrome (CRS) is affecting a large proportion of patients and is receiving much attention in clinical research in recent years. The deep-diving hooded seal has been shown to have exceptional hypoxia tolerance, an adaptation to its diving life-style, and the resulting physiological resiliency makes them highly interesting for clinical research. One of their physiological adaptations is exceptional cardiovascular control, whereby blood is redistributed to hypoxia sensitive tissues (e.g., brain and heart) at the expense of more hypoxia-tolerant organs, of which the kidney is one. This makes this species an ideal animal model to study how their kidney is adapted to survive ischemia during diving, and the following reoxygenation, apparently without sustaining damage. Hypoxia leads to elevated lactate levels due to increased anaerobic metabolism, and the lactate receptor HCAR1 has been shown to exert cardiovascular control in the kidney in dogs, as well as having a neuroprotective effect in response to hypoxia. Furthermore, HCAR1 is involved in the regulation of lipid-droplets (LD) metabolism, which has been shown to protect from reactive oxygen species (ROS). ROS are a primary problem during reoxygenation after hypoxia due to ROS production in mitochondria.
We therefore aim to apply heart/kidney surgery (well established in clinical research on pigs, see FOTS 18620) on hooded seals in a terminal model producing cardiac arrest that will lead to kidney ischemia.
The aim of this pilot is to adapt and refine the surgical procedure used on pigs for use in seals, where the access to the relevant blood vessels and organs is slightly different. If this pilot study succeeds, we will apply for a full experimental FOTS to investigate the role of lactate-induced HCAR1 activity and LD regulation in ischemia in the heart and kidney of seals, and hypothesize that both are contributing to hypoxia tolerance in hooded seals.
2 Skadevirkninger
No animal welfare issues expected since this is a terminal experiment
3 Forventet nytteverdi
The results from this project will contribute to improve clinical treatment of cardiorenal syndrome (CRS) in human patients and will also shed more light on the evolutionary adaptations that enable diving mammals to hold their breath for 1-3 hours..
4 Antall dyr og art
4 hooded seals (Cystophora cristata) of any age/size
5 Hvordan etterleve 3R
The integrated cardiovascular control is only possible to study in the intact animal.
All animals will be sacrificed for other scientific purpose independent of this pilot-project, i.e. no additional animals will be needed. All procedures will be performed in full surgical anesthesia and no extra strain will be put on the animals.
Knowledge gained from this pilot project will ensure a refined protocol for the follow-up project and enable us to secure that complications are avoided, animal welfare is maintained and scientific data collection and sampling is optimized.
Cardiovascular disease is still the leading cause of premature death in the western world. The kidney is one of the first organs to disfunction in fatal cardiac arrest, the main problem being inadequate perfusion and resulting ischemia. The resulting cardiorenal syndrome (CRS) is affecting a large proportion of patients and is receiving much attention in clinical research in recent years. The deep-diving hooded seal has been shown to have exceptional hypoxia tolerance, an adaptation to its diving life-style, and the resulting physiological resiliency makes them highly interesting for clinical research. One of their physiological adaptations is exceptional cardiovascular control, whereby blood is redistributed to hypoxia sensitive tissues (e.g., brain and heart) at the expense of more hypoxia-tolerant organs, of which the kidney is one. This makes this species an ideal animal model to study how their kidney is adapted to survive ischemia during diving, and the following reoxygenation, apparently without sustaining damage. Hypoxia leads to elevated lactate levels due to increased anaerobic metabolism, and the lactate receptor HCAR1 has been shown to exert cardiovascular control in the kidney in dogs, as well as having a neuroprotective effect in response to hypoxia. Furthermore, HCAR1 is involved in the regulation of lipid-droplets (LD) metabolism, which has been shown to protect from reactive oxygen species (ROS). ROS are a primary problem during reoxygenation after hypoxia due to ROS production in mitochondria.
We therefore aim to apply heart/kidney surgery (well established in clinical research on pigs, see FOTS 18620) on hooded seals in a terminal model producing cardiac arrest that will lead to kidney ischemia.
The aim of this pilot is to adapt and refine the surgical procedure used on pigs for use in seals, where the access to the relevant blood vessels and organs is slightly different. If this pilot study succeeds, we will apply for a full experimental FOTS to investigate the role of lactate-induced HCAR1 activity and LD regulation in ischemia in the heart and kidney of seals, and hypothesize that both are contributing to hypoxia tolerance in hooded seals.
2 Skadevirkninger
No animal welfare issues expected since this is a terminal experiment
3 Forventet nytteverdi
The results from this project will contribute to improve clinical treatment of cardiorenal syndrome (CRS) in human patients and will also shed more light on the evolutionary adaptations that enable diving mammals to hold their breath for 1-3 hours..
4 Antall dyr og art
4 hooded seals (Cystophora cristata) of any age/size
5 Hvordan etterleve 3R
The integrated cardiovascular control is only possible to study in the intact animal.
All animals will be sacrificed for other scientific purpose independent of this pilot-project, i.e. no additional animals will be needed. All procedures will be performed in full surgical anesthesia and no extra strain will be put on the animals.
Knowledge gained from this pilot project will ensure a refined protocol for the follow-up project and enable us to secure that complications are avoided, animal welfare is maintained and scientific data collection and sampling is optimized.