Your heart does not beat in isolation. As it tirelessly pumps blood throughout the body, this vital organ intricately connects with others, including the kidneys. But when the heart falters, these delicate balances become disrupted, potentially impairing the kidneys as well. Now, scientists are leveraging innovative “organ-on-a-chip” devices to illuminate how heart dysfunction exacts a toll on kidney health, uncovering new treatment targets along the way.
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At Massachusetts General Hospital (MGH), a team led by Dr Emeli Chatterjee in Dr Saumya Das’s laboratory is investigating kidney disorders related to a condition called heart failure with preserved ejection fraction (HFpEF). Despite the heart contracting normally, it struggles to relax and refill with blood in HFpEF. This not only strains the heart but also disrupts interconnected organs like the kidneys.
However, modelling the influence of a dysfunctional heart upon kidney health in animal studies has proven unsuccessful. As Dr Michail Spanos, physician-researcher at MGH, explains, “When kidneys from HFpEF patients are transplanted into healthy recipients, they function normally, suggesting factors beyond the kidneys are at play.”
Recent discoveries indicate tiny particles in the blood called extracellular vesicles (EVs) might enable crosstalk between organs. Studying their role in HFpEF could unlock new protective therapies for associated kidney dysfunction.
By collecting blood samples from individuals with and without HFpEF, the researchers isolated EVs for analysis. They introduced HFpEF-derived EVs into a specialised “kidney-on-a-chip” model to observe their effects on kidney cells.
“This study is the first to recognise that extracellular vesicles from individuals with HFpEF-CRS directly contribute to causing kidney injury,” says Dr Emily Chatterjee.
In search of a cure
The research revealed that EVs from individuals with heart and kidney issues contained specific microRNAs capable of influencing genes and pathways associated with kidney injury. “We concluded that these microRNAs play a significant role in regulating overall kidney function, reflected in plasma creatinine levels,” says Dr Chatterjee.
But while the EV-related microRNAs were seen as a possible cause for kidney dysfunction, they could also be useful in its therapy.
Researchers discovered that using specific miRNA inhibitors and mimics could either reduce or mimic the influence of these EV-related microRNAs on kidney cells. Targeting these molecules with RNA therapies led to improved kidney cell health, resembling those found in individuals without heart issues.
One potential outcome could involve developing therapies using EV-carried microRNAs to mitigate kidney injury in those with HFpEF. Furthermore, these EVs might serve as potential biomarkers for CRS, offering promise for future diagnostic and treatment approaches.
Dr Saumya Das, the senior investigator and corresponding author noted, “These organ-on-chip platforms provide a unique opportunity to study the functional role of EVs in human diseases, and can cover novel pathways of disease that could be the targets of new drugs.”
A surrogate for every organ
Dr Spanos foresees significant advancements in the organ-on-chip model technologies: “The kidney-on-chip is just the tip of the iceberg. These chip models present a groundbreaking avenue for studying not only diseases but also the responses of different organs to specific treatments and medications. The potential is vast, as each chip could act as a surrogate for its respective organ, allowing for precise and personalised medicine. It’s an important step towards understanding organ interplay and systemic responses in complex conditions such as CRS.”
