NephCure Funded Research: Dr. Evren Azeloglu April 3, 2017 by Lauren Eva NephCure Funded Research: Dr. Evren Azeloglu Dr. Evren U. Azeloglu In 2015, Dr. Evren Azeloglu, a biomedical engineer and an Assistant Professor at the Icahn School of Medicine at Mount Sinai, was awarded the NephCure Kidney International-ASN Foundation for Kidney Research Grant. He planned to use this grant to explore how kidney cells retain their structural integrity against mechanical injury. Much of the work done in Dr. Azeloglu’s lab involves the podocyte, the specialized kidney cell that is affected by glomerular diseases like FSGS. Podocytes play an important role in glomerular function. Together with other cells, they help form a filtration barrier in the kidney, and they cooperate with other cells to support the structure and function of the glomerulus. Below, we discuss Dr. Azeloglu’s latest research and what it means for people living with glomerular kidney diseases in our search for better treatments and a cure. NKI: You’ve recently released two articles (here and here), both from research funded in part by NephCure. Can you tell us about your latest research? Dr. Azeloglu: Well, podocytes have a very beautiful structure, and we used cutting-edge imaging technology to capture the three-dimensional geometry of these cells. This paper is essentially about how the podocyte shape is not just pretty and sophisticated, but also very necessary for their function. And their shape has certain consequences for disease: some of the glomerular diseases may be directly borne out of the fact that these cells are shaped this way. If you look at the below gif, you will see how these cells look in the body. This is the first time anyone has ever visualized them with this kind of precision. NKI: Can you elaborate on what you mean when you say that their form suits the function? Dr. Azeloglu: Well let’s say that you want to build a drawbridge, and you want to be able to have tall ships travel below or through it. So you can either spend a lot of money and build a very tall bridge that is stationary, or you can build one that opens and closes. Basically, you are proposing a “functional upgrade” to a regular bridge. Unfortunately, that comes at a cost. The bridge needs to be able to separate in the middle. Following that analogy, podocytes have this special shape that allows them to do something that no other cell can do. What we are showing in our paper is that this special shape also comes with a price: incredible fragility. This works in the same way that a drawbridge has less stability than a regular arched bridge and would not be able to sustain the same level of, for example, an earthquake. You sacrifice that stability because you want to be able to open it up. In the same way, podocytes have incredible surface area; they have this amazing structure that allows them to filter blood plasma into urine, but what we’re showing is that only at this shape, the cells start showing this incredibly fragile behavior, and even a little change of their chemistry leads to disease. This ties in very well with the current knowledge that the podocytes are sort of the first guys to fail, if you will. This is one of the reasons why, for example, diabetic patients, whose cells are under constant stress because of insulin spikes, high levels of glucose, and all sorts of other oxidizing agents, are much more likely to develop nephropathy. So, what we are trying to show here is that these cells are incredibly fragile compared to most other cells in our body. NKI: What does it mean to be a biomedical engineer studying podocytes, and from a larger perspective, kidney disease? Dr. Azeloglu: I approach kidney research from an engineer’s perspective: the same way we study machines, buildings, and structures that have to withstand physical stress, which is exactly what podocytes have to do day in and day out. What we’re looking for, and what most of the projects in my lab focus around is: can we understand what makes these cells more susceptible to physical damage, and perhaps reinforce their structure? When all’s said and done, podocytes form a filter, which has a biological function, but to achieve that function, the podocyte uses a very simple physical mechanism: forming a sieve. So we ask, can we come up with therapeutic strategies that can make the podocytes stronger and more resilient? Or can we identify how specific chemical and biomechanical assaults weaken them? NKI: So is your lab directly looking at ways to fortify the cell? Or is that something you’re laying the groundwork for, for someone else to build from. Dr. Azeloglu: To be able to fortify something, you want to be able to understand it first. There’s been a lot of science over the last two decades showing that a lot of what these cells do is basically prepare for constant physical abuse, for lack of a better word. It’s just not very pleasant to be a podocyte. It’s biologically expensive to try to maintain physical integrity. So “Part One” of my lab’s research program is: to try to understand what makes these cells unique and special, what is the repertoire of these cells for withstanding physical stress. And “Part Two” is: if we can understand it, can we eventually fortify it? Can we prevent this structure from failing under disease conditions? These cells are very fragile, and they need all the help they can get. We’re expecting them to stick around for 80 years — that’s a long time to be under constant physical abuse. Dr. Azeloglu (pictured second from left) and his Systems Bioengineering Laboratory team at the Icahn School of Medicine at Mount Sinai. NKI: The podocyte is such a specific cell—how did you become interested in studying it exclusively? Dr. Azeloglu: Partly because of the video that you’re looking at—they’re really unique. They’re also almost a poster child of physical cellular stamina. They’re a great example of a microscopic structure that has evolved to do a very specialized physical task and do it for an extended period of time. It’s sort of a dream come true for an engineer. NKI: What stage were you at in your research when you received this award? Did it have a big impact on what you were able to do? Dr. Azeloglu: Oh, absolutely! I had just received my appointment as an Assistant Professor, and I had just started setting up my own lab. Without this, I basically wouldn’t have been able to do that. I come from a cardiac background—as a biomedical engineer, I trained in a cardiac biomechanics lab. And the heart, being a mechanical pump, is another example of a living tissue that’s doing a physically demanding job. I studied that for ten years and as I was transitioning into nephrology, the NephCure-ASN Award was critical. It helped me establish myself as an expert in this field as well. It’s sort of a rite of passage—a lot of the fellows who’ve received this award have moved on to successful careers, so it’s almost expected for you to have one to establish yourself in the field. I also think my goals and the goals of the NephCure-ASN Award align very well. I want to understand these cells from an engineer’s perspective, which I think is very relevant to their function, and if we can understand it, I think we’ll be able to cure diseases like FSGS. We’ll be able to not only help patients in terms of their symptoms, but also actually cure the disease. I’m in a pharmacology department, so I know that our standard methods can only help us so far; hopefully, this new, fresh perspective will be able to take us to the next level: instead of just dealing with the symptoms, we’ll be able to cure kidney disease. Hopefully. We were delighted to speak with Dr. Azeloglu on the results of his current research. If you want to stay updated on his work, you can follow him on Twitter (@azeloglu) or visit his lab’s website at http://labs.icahn.mssm.edu/azeloglulab. Thank you for your dedication to this work, Dr. Azeloglu and team! Dr. Evren U. Azeloglu is an Assistant Professor in the Department of Pharmacological Sciences at the Icahn School of Medicine at Mount Sinai. He was originally trained as a mechanical engineer, but later went on to receive his Ph.D. in biomedical engineering from Columbia University. In 2010, Dr. Azeloglu was awarded the Howard Hughes Medical Institute Fellowship from the Life Sciences Research Foundation. His background in biomechanics and systems biology is uniquely positioned to study complex diseases such as hypertension and diabetic nephropathy. He aspires to design transformative therapeutic tools using nanotechnology and tissue engineering.