How kidney cells regulate cardiac function: An insightful message from the flies

Work done in the lab of Dr. Sudip Mandal at the Indian Institute of Science Education and Research Mohali (IISER Mohali).

About author

Jayati Gera belongs to a small town known as Yamuna Nagar, located in Haryana, India. She pursued her Bachelor’s in Biotechnology Engineering from the University Institute of Engineering and Technology (UIET), Panjab University, Chandigarh. Subsequently, she joined Dr. Sudip Mandal’s research group at the Indian Institute of Science Education and Research Mohali (IISER Mohali) for her Ph.D. During her doctorate, she worked on understanding the regulation of pericardin (collagen IV in flies) homeostasis using adult Drosophila melanogaster as a model system.

Interview

How would you explain your research outcomes to the non-scientific community?

Reactive oxygen species (ROS) are oxygen-containing, highly reactive, and unstable molecules generated as a byproduct during different metabolic events in a cell. To overcome the harmful effects of generated ROS, cells employ a sophisticated antioxidant defense mechanism. Over the last several decades, ROS species have been known for their damaging properties as they possess the capability to react with macromolecules such as DNA, RNA, and proteins within a cell. However, in the last few years, scientists have also appreciated the role of ROS as mediators of numerous biological responses. Therefore, ROS is no longer just an unwanted byproduct of an imbalanced system but a vital metabolite that plays a crucial role during different developmental processes.

Like all other organs, the heart is surrounded by the extracellular matrix (ECM) components which comprise collagen, elastin, laminin, glycoproteins, and other biomolecules. These ECM components help maintain proper integrity and function of the cardiac tissue. Therefore, understanding ECM regulation is of prime importance. Similar to the higher vertebrates, one of the essential cardiac ECM components in fruit-flies Drosophila is a type IV collagen protein- Pericardin. Despite the fact that it plays a critical role in maintaining cardiac integrity, the mechanism regulating pericardin expression is still unknown. Thus, employing the Cinderella of genetics-Drosophila melanogaster, we attempted to unravel this mystery. In the process, we were able to decipher a fascinating mechanism by which the high levels of physiological ROS present in the pericardial cells, also known as nephrocytes (kidney cells), play a vital role in controlling cardiac function. This is achieved by releasing the cytokine Upd3 from the nephrocytes, which triggers pericardin expression in the fat cells. Hence, our study not only sheds light on an elegant mechanism by which the metabolic state of the kidney regulates cardiac function and a healthy lifespan but also highlights the involvement of ROS in cytokine dependent ECM regulation during normal development.

Model showing the inter-organ communication circuitry connecting the pericardial cells and the fat cells to regulate cardiac function by controlling Pericardin deposition in the cardiac ECM of adult flies. This elegant inter-organ crosstalk gets triggered by high levels of physiological ROS in the pericardial cells. Ask1 senses this high pericardial ROS and, in turn, activates two independent MAPKs- JNK and p38 pathways to regulate upd3 expression. Upd3, a secretory cytokine, goes through the hemolymph to the fat body cells and activates the JAK/STAT signaling pathway, resulting in pericardin transcription. Finally, the protein Pericardin gets synthesized and secreted by the fat cells and forms the ECM meshwork around the cardiac tissue.

How do these findings contribute to your research area?

In order to maintain systemic homeostasis, proper coordination between different organs is essential. Such kind of physiologically relevant crosstalk between the kidney and the heart is demonstrated in our study. Unlike mammals, the Drosophila heart is a part of an open circulatory system. Therefore, all the organs are bathed with hemolymph- blood in the case of flies. The contractions of the cardiac tissue pump the hemolymph into the body cavity, which carries the necessary nutrients, metabolites, hormones, etc., to all the peripheral organs. Like the higher vertebrates, hemolymph contains toxic materials that get filtered and destroyed by the pericardial cells (filtration unit in Drosophila). Therefore, there is a need to coordinate the functions of these two vital organs to maintain normal physiology. In this way, depending upon the filtration capacity, the kidney can signal the heart to slow down or increase the cardiac flow accordingly. In a sense, this appears to be a primitive version of the heart-kidney link observed in higher vertebrates.

Thus, in future studies, it would be interesting to further explore this model system to study the impact of diet alterations or metabolic disorders such as diabetes and obesity on the crosstalk between these vital organs, thereby affecting ECM turnover, as excessive ECM deposition can result in pathological conditions like cardiac fibrosis and heart failure.

“our study not only sheds light on an elegant mechanism by which the metabolic state of the kidney regulates cardiac function and a healthy lifespan but also highlights the involvement of ROS in cytokine dependent ECM regulation during normal development.”

What was the exciting moment during your research?

Honestly, there were several exciting moments. I thoroughly enjoyed my research journey, as it was a great learning experience. One of the first exciting moments for me was when I genetically lowered the levels of cytokine Upd3 in the pericardial cells, and I could see the reduced pericardin levels in the fat cells accompanied by reduced Pericardin deposition around the cardiac tissue. Until that moment, I had just read about the concept of inter-organ communication in a few research papers. It was so fascinating for me to witness how the manipulations in the kidney cells could alter the cardiac ECM by involving another cell type- the fat cells.

What do you hope to do next?

As I already mentioned, the field of inter-organ communication has always been fascinating for me, and I have just started to understand its intricacies. There is still a long journey ahead of me. Thus, I wanted to explore it further by understanding the different communications controlled by the brain by gaining some expertise in neurobiology and behavior in the coming few years.

Where do you seek scientific inspiration from?

Like any other explorer or researcher, I have always enjoyed solving puzzles and mysteries, even when I was a kid. The excitement of being the first one to unravel the mystery before it gets exposed to others is simply unbeatable. In a way, it helps me keep my inner child happy and lively.

Most importantly, my father has been a great source of inspiration for me since my childhood days. He has always encouraged me to follow my passion, even if it means following the less followed path. He has been my biggest teacher, and one of the most important teachings that I have learned from him is to contribute to the upliftment of society in one way or another. So, I decided to choose my research as a means to serve my society, my country and make him proud of me.

How do you intend to help Indian science improve?

Undoubtedly, Indian science has improved immensely in the last few years. However, there is still a need for more national and international collaborative as well as interdisciplinary work to further promote science and technology in India. I would like to inculcate awareness among young minds to inspire them to pursue scientific research as their career choice. India has no dearth of bright young minds with infinite capabilities; they just need proper exposure during their early career and ample opportunities to build a better future.

Reference

Jayati Gera, Prerna Budakoti, Meghna Suhag, Lolitika Mandal, and Sudip Mandal. Physiological ROS controls Upd3-dependent modeling of ECM to support cardiac function in Drosophila. ScienceAdvances (2022). https://www.science.org/doi/10.1126/sciadv.abj4991

Edited by: Anjali Mahilkar

Meet the managers

Surabhi Sonam

Surabhi Sonam is an Assistant Professor. Along with teaching and research, she has a very strong interest in science communication. She has written several poems and blogs to communicate scientific principles and concepts. She is also volunteering with several science communication platforms as a content contributor and content editor. Under her supervision, her students have launched a scicomm magazine, Scinion which represents science in verbal and visual forms.

Sejal Dixit

Sejal Dixit is currently a 3rd-year student pursuing BSc triple majors in biotechnology, zoology, and chemistry from CHRIST (Deemed to be University). She loves to read, be it short stories, novels, magazines, or research articles. She is working with her college professor on a few papers, and wishes to pursue her master’s degree in stem cells and regenerative medicines. She has no problem socializing with new people and possesses leadership qualities. Her hobbies are dancing and traveling.

For interview related queries, write to us at interview.biopatrika@gmail.com