by Kyoto University

Pathological changes in podocytes and albuminuria after ischemia reperfusion injury (IRI). Credit: Nature Communications (2024). DOI: 10.1038/s41467-024-54222-0

Acute kidney injury (AKI) often occurs as a result of ischemia, which is a condition in which blood flow to part of the body is restricted, depriving tissues of oxygen and nutrients. This damage is commonly followed by reperfusion (that is, the restoration of blood flow), but this process can sometimes exacerbate injury through oxidative stress and inflammation. This is called ischemia-reperfusion injury.

AKI remains a significant clinical challenge with limited treatment options and poor outcomes. Recent studies suggest that proteinuria, where protein leaks into the urine, is a common feature and associated with poor long-term renal prognosis after AKI. However, the mechanisms underlying proteinuria and its links to kidney cell damage are still unclear.

In a new study published in Nature Communications, researchers in Japan led by Dr. Motoko Yanagita focused on the role of podocytes, which are specialized kidney cells crucial to filtering blood. In particular, they looked at the energy requirements of these cells during ischemia-reperfusion injury.

Podocytes are suggested to rely on adenosine triphosphate (ATP), the main energy carrier in cells, to maintain their structural integrity and filtration functions. Using advanced imaging technologies, the researchers revealed how energy imbalances in these cells contribute to kidney damage.

The team performed imaging on living animals (intravital imaging) and used genetically modified mice expressing a fluorescent ATP biosensor to measure real-time changes of ATP in podocytes during ischemia-reperfusion injury. Female mice were used because the outer layer of their kidneys, the renal cortex, is thinner compared with that of males, which makes females better suited for imaging of the filtering units within the kidney where podocytes are located.

Their experiments showed that ATP levels in podocytes gradually declined during ischemia and failed to sufficiently recover after prolonged ischemia, especially in the super-acute phase immediately following restoration of blood flow.

This ATP insufficiency was associated with mitochondrial fragmentation, a structural disruption in the cell's energy-generating organelles. In addition, the study linked this energy imbalance to a "flattening" of key podocyte structures, which is known as foot process effacement. This disrupts the filtration function of the podocytes and is associated with proteinuria.

"We observed that insufficient ATP recovery in the super-acute phase of ischemia reperfusion injury correlates strongly with foot process effacement in podocytes," said Dr. Masahiro Takahashi, the first author of the study. "This finding suggests that disrupted ATP dynamics are associated with structural changes of podocyte foot processes and the leakage of protein into the urine during acute kidney injury."

The study also found that interventions targeting mitochondrial dynamics held promise. By using drugs to suppress mitochondrial fragmentation, researchers were able to alleviate foot process effacement and improve podocyte outcomes both in vivo (in the mice) and ex vivo (outside the mice). These findings point to the potential of mitochondrial-focused therapies in protecting podocytes from ischemia-reperfusion injury.

"This research shifts the focus from the tubular, which has been a central focus in previous studies, to the relatively understudied podocyte," Dr. Takahashi explained. "We hope that our research will bring attention to podocyte as a key factor in AKI and expand the scope of AKI research in relation to its prognosis and progression."

In future research, the team plans to investigate ATP dynamics in other forms of AKI, such as AKI induced by drugs or sepsis, which could provide additional insights into the disease's complexity. The researchers are also working on experiments with podocyte-specific transgenic mice to better understand how these cells influence long-term kidney outcomes after injury.

"ATP dynamics and their influence on podocytes in these different types of AKI are still elusive," adds Dr. Takahashi. "We hope that our research sheds light on podocyte in AKI and provides new directions for AKI research."

The study represents a significant advance in understanding how energy imbalances in kidney cells contribute to disease, offering new perspectives on potential therapeutic strategies for a condition that affects millions of people worldwide.

More information: Masahiro Takahashi et al, ATP dynamics as a predictor of future podocyte structure and function after acute ischemic kidney injury in female mice, Nature Communications (2024). DOI: 10.1038/s41467-024-54222-0

Journal information: Nature Communications 

Provided by Kyoto University