Mitochondrial Medicines against Acute Kidney Injury

Summary

Acute kidney injury (AKI) is a critical clinical syndrome characterized by the rapid loss of the kidney's excretory function and is typically diagnosed by the accumulation of end products of nitrogen metabolism (urea and creatinine) or decreased urine output. Mitochondrial dysfunction and damage of renal tubular cells, reflected by the increased excretion of mitochondrial DNA (mtDNA) in urine, is an established feature of AKI. Mitochondrial damage is reflected in rapid tubular mitochondrial fragmentation and shortening, the decrease in mitochondrial membrane potential and respiration and excess production of mitochondrial reactive oxygen species (ROS); both culminating in a state of oxidative stress, characterized by ATP depletion, lipid peroxidation, and the release of proapoptotic proteins that contribute to the development and progression of AKI.
A natural defense mechanism against oxidative stress-induced organ damage can be found in hibernating animals, i.e. hibernating animals can maintain mitochondrial function, ATP levels and do not show signs of organ damage, while being under great stress. Kidney tubule cells from hibernators have an increased resistance to oxidative stress compared to non-hibernators, which might originate from differences in mitochondrial morphology and function between hibernating and non-hibernating species. Based on our research into hibernation, we have identified a chemical entity which is capable of inducing the mitoprotective effects observed in hibernating species to non-hibernating species. These 6-hydroxychromanols might thus offer great therapeutic benefit in diseases where mitochondrial function is hampered. In the proposed project, we will elucidate the molecular mechanism behind the mitoprotective effects of 6-hydroxychromanols and provide proof-of-concept for the application of 6-hydroxychromanols as therapeutics against AKI.

Details

Project number

NWA.ID.17.093

Main applicant

Prof. R.H. Henning

Affiliated with

Rijksuniversiteit Groningen, Universitair Medisch Centrum Groningen, Klinische Farmacie en Farmacologie

Duration

06/08/2018 to 04/08/2023