QnAs with Andrew P. McMahon

The kidney plays a crucial role in the body, filtering waste and toxins from the blood and maintaining homeostasis. However, the kidney has a limited capacity to repair itself, which can turn acute injuries into long-term disease. Acute kidney injury has emerged as a global health concern and affects 13.3 million people worldwide, and chronic kidney disease, for which there are no therapies, results in 1.2 million deaths each year. University of Southern California (USC) professor of stem cell biology and regenerative medicine, Andrew P. McMahon, has leveraged an understanding of how organs develop to shed light on how kidneys form and how they respond to injury. His work focuses on an understanding of normal kidney development and repair processes triggered by injury to improve disease modeling and identify novel therapeutic targets. McMahon was elected to the National Academy of Sciences in 2020. PNAS recently spoke to him about his current research.

Andrew P. McMahon. Image credit: Jill McMahon (photographer).

PNAS: Your Inaugural Article details the fate of proximal tubule cells following an acute kidney injury (1). What role do these cells play in the kidney?

McMahon: Proximal tubule cells are the predominant cell type of the nephron, which is the functional unit of the kidney. They help maintain electrolyte balance and fluid homeostasis and have high metabolic activity. They are also especially susceptible to injury and ischemia, a lack of blood supply.

Unlike some other organs, the adult kidney does not have stem cells that would help it repair. Instead, differentiated proximal tubule cells play this role. They can enter a repair process in response to injury, restoring kidney architecture and function. But they do not do so flawlessly. The repair feature is limited. Some proximal tubule cells are never fully capable of bouncing back and making proper nephron cells. Instead, they enter a state of persistent injury, an inflammatory state, where they continue to excite the body’s immune system in a pathological manner that eventually can lead to chronic kidney disease.

PNAS: What were you able to uncover about the contribution of these cells to the progression of chronic kidney disease?

McMahon: In the article (1), we were able to identify and characterize two groups of injured proximal tubule cells: ones that arose shortly after injury, and others that appeared later, in a different part of the kidney, in areas that weren’t associated with primary injury. Both the early- and late-arising cells had features of senescence and produced proinflammatory cytokines, such as Ccl2. We believe that inflammatory-associated senescence is a key feature of immune-based damage to the kidney. Our broad conclusions based on a mild-to-moderate injury agree well with those of the Humphreys group at Washington University studying a more severe injury and published in PNAS last year (2)

It’s a snowball effect. First, you have a small population of injured cells from the acute injury event that excite the immune system, which creates more damage. And then you transition from a simple injury that underwent some level of repair: actually, a good level of repair if you were to measure the kidney physiologically. But, over several years in a patient the kidney gradually succumbs to chronic disease and a loss of function.

PNAS: You have used genetic tools throughout your career to study development. How did they come into play in this research?

McMahon: There haven’t been efficient genetic tools to study the progression from acute kidney injury to chronic kidney disease. In this work, we developed a method to track cells by genetically targeting a gene encoding the protein keratin-20, which we had previously identified as a marker of injury. This targeting allowed us to follow injured cells over time and isolate them at different points during the kidney repair process. We then performed single nuclear mRNA sequencing on these cells to characterize the transcriptional profiles associated with kidney injury and repair. We also used another mouse strain to track the fate of dividing cells initiating repair. This approach highlighted regional and temporal differences in proximal tubule injury.

These genetic tools facilitated finding the relevant cells—like looking for a needle in a haystack—and provided additional insight into the evolution of cellular responses invoked by a short burst of ischemia. Precise, single-cell spatial genetics and genomics is, I think, going to be a big driver of our insight into complex biological problems over the next 5 to 10 years.

PNAS: How might this research inform therapeutics to treat chronic kidney disease?

McMahon: First, this research presents a more dynamic picture of how the initial injury event, even if mild, leads to the creation of a persistent injured cell type that most likely contributes to long-term disease progression. It might be like radioactivity: There’s no safe level for the initial injury, given sufficient time for disease progression.

There are a couple of features of the cells, however, that make them potentially attractive for therapeutics. Perhaps we can target these cells for destruction by the immune system. Research has shown that activating killer T cells to destroy injured liver cells promotes recovery. This approach could be broadly beneficial as this inflammatory senescent phenotype has been observed in cardiac injury as well.

Like cancer cells, the cells failing to functionally repair following kidney injury may suppress cell death and apoptosis, promoting activities to survive. Could removing apoptosis-suppressing genes, which we have identified in injured proximal tubule cells, trigger programmed cell death and limit disease progression? There may not be full recovery of the kidney in this case, but halting chronic disease onset at an early stage, which could be identified by biomarkers, would certainly be beneficial.

PNAS: You started working on kidneys in 2012. How did you become interested in this organ, and how does this work fit into the broader context of your research?

McMahon: The kidney is a complex system with a lot of potential for therapeutic intervention. Perhaps because of that complexity, however, it has been somewhat neglected by biotech and pharmaceutical companies. While there was interest in the organ a few decades ago, interest has revived of late. There are many likely reasons for this revival. One is certainly that we now have organoid systems that can potentially model the complexity of disease progression more faithfully than the long-established laboratory cell lines have in the past. I think that now is a very good time to be digging deeper into these systems.

Prior to USC, I had worked on many different organ systems, mostly from the perspective of how cells coordinate their behaviors to give rise to organs. When I joined the medical school faculty here, I redirected my research toward clinical end-points rather than purely academic questions. The kidney had always attracted me, in particular the dynamic nature of how the structure develops. And the absence of drugs and therapeutics seemed like a great area on which to focus my work. There is so much opportunity to make a difference in the kidney, and this opportunity gives great scope for trainees to set up their own [laboratories] and establish their own programs in a field that is not overcrowded by any means.