Uncovering a protective RNA molecule in kidney stress and disease

Guoping Li, PhD, of the Department of Anesthesia, Critical Care & Pain Medicine at Massachusetts General Hospital, is the lead author and Saumya Das, MD, PhD, of the Cardiovascular Research Center at Massachusetts General Hospital, is the senior author of a paper published in Science, A hypoxia-responsive tRNA-derived small RNA confers renal protection via RNA autophagy.

Q: How would you summarize your study for a lay audience?

Cells contain helper molecules called transfer RNAs (tRNAs), which carry building blocks (amino acids) to make proteins. These tRNAs can be broken down into smaller pieces called tRNA-derived RNAs (tsRNAs or tDRs) that have new jobs - to help cells deal with stress and challenging situations.

In this study, we focused on one specific tDR, called tRNA-Asp-GTC-3'tDR, which becomes more abundant during stress. tRNA-Asp-GTC-3'tDR is present at baseline in kidney cells and increases in response to disease-related stress signals in cell culture and several mouse models of kidney diseases. Importantly, its levels are also higher in human conditions like preeclampsia and early kidney disease.

tRNA-Asp-GTC-3'tDR helps protect kidney cells by regulating a critical process called autophagy, where cells break down and reuse their own parts. Blocking tRNA-Asp-GTC-3'tDR in kidney disease models led to more kidney damage, including cell death, inflammation, and scarring.

To test if boosting this tDR could help, we developed a way to increase its levels in mouse kidneys. Mice had more kidney protection with less scarring, inflammation, and injury when this tDR was present at higher levels.

We also learned that the tDR's unique folded shape, called a G-quadruplex, is essential for its protective effect. This shape helps it bind to proteins that manage autophagy, making it a potential new target for kidney disease treatments in the future.

Q: What question were you investigating?

We sought to determine the regulation and function of the novel tRNA-Asp-GTC-3'tDR that increases markedly with stress in different cell types and is expressed at high levels at baseline in metabolically active tissues and cells.

Q: What methods or approach did you use?

We developed new tools to assess its biogenesis, reagents to silence this molecule selectively using machine learning approaches and deliver/increase its levels. These tools allow precise control of its levels to investigate its role and therapeutic potential in cell culture and disease models.

Q: What did you find?

We found that the hypoxia-responsive tRNA-Asp-GTC-3'tDR maintains cellular homeostasis in kidney cells by regulating autophagic flux and plays a key role in the stress response. The levels of tRNA-Asp-GTC-3'tDR increased acutely in animal models and human cell cultures to enhance autophagic flux and protect against cellular injury, inflammation and fibrosis.

Q: What are the implications?

We identified a promising RNA molecule that could be therapeutically targeted to treat patients with kidney diseases, such as chronic kidney disease.

Q: What are the next steps?

We are developing platforms and tools to study the therapeutic potential of this tDR in kidney and heart disease. These new tools will help determine safety, durability and any toxicity of treatments. Additionally, we are developing Cas13-based RNA editing tools to enhance the expression of the endogenous tDR, a far more efficient way to manipulate the cell's own tDR.