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Acute Kidney Injury Research

February 27, 2019

Sunder Sims-Lucas, PhD, is an assistant professor of pediatrics in the Division of Pediatric Nephrology. A developmental biologist by training with a focus on the kidney, Dr. Sims-Lucas also holds appointments in the University of Pittsburgh Department of Developmental Biology, the Clinical and Translational Science Institute, and the Center for Critical Care Nephrology. Dr. Sims-Lucas operates a broad portfolio of research interests, many with related and interrelated themes.

His postdoctoral research at UPMC Children’s focused on fibroblast growth factor receptors in kidney development, and upon joining the Division as full-time faculty in 2013, his laboratory began investigating aspects of the different types of developing vasculature, identifying a novel subset of endothelial progenitors that are critical for repair after an acute kidney injury (AKI).

Since his early days with the Division, Dr. Sims-Lucas’ research has progressed and expanded into a host of related themes that deal with vasculature development, acute kidney injury, hypoxia and nephrogenesis, and endothelial progenitors in the developing kidneys and lungs and in their diseases, among others. The goal of much of this research is to ultimately develop new therapies that could be used to mediate acute kidney injury or help stimulate repair of injured kidney tissues following AKI.

Beyond his bench research responsibilities and interests, Dr. Sims-Lucas serves as the director of student research training at UPMC Children’s. In this capacity, he oversees training programs for students in high school through to postdoctoral researchers. Dr. Sims-Lucas indicates that this year they have applied for NIH funding to train undergraduates from the current summer program at UPMC Children’s (which he has run for the past four years) in a break-off program, placing them in various laboratories across the University of Pittsburgh to study the science of kidney formation and various diseases of the kidney.

Endothelial Progenitor Research and Acute Kidney Injury

The developing vasculature gives rise to many different types of mature vessels, and this has been a focus for the Sims-Lucas laboratory. Past work on the nature of vascular development by Dr. Sims-Lucas was able to identify a novel subset of endothelial progenitors which proved to be critical to normal formation. “Deleting a key gene for these progenitors in animal models caused endothelial cell malformation, leadingto incorrectly formed vessels and making the model very susceptible to damage.” In  essence, what Dr. Sims-Lucas’ research points to is that an individual may have a developmental insult that is sub-pathological in nature — until a secondary stressor like AKI occurs, leading to a further decline in kidney function.

Oxygenation and Hypoxia

Another central focus of Dr. Sims-Lucas’ research is the role of oxygenation in hypoxia within the broader theme of vascular development and organ perfusion. Ischemic injury in AKI can very quickly cause cellular damage. “When they do become damaged through hypoxia, several interesting things happen. These cells undergo a differentiation back to an early developmental stage and begin expressing immature markers. The cells do this in order to become proliferative again, thus instigating a repair process, repopulating the damaged tubule in the kidney and subsequently re-differentiating to complete the repair process. So, we are very interested in how this process works, and why, and perhaps we can one day control or manipulate it to repair damage from AKI.”

Gene Mediation and AKI

In progress research by Dr. Sims-Lucas and his laboratory is probing a family of genes called the sirtuins and their possible protective role in AKI. “The sirtuin genes have been linked to a number of processes related to aging, metabolic defects, and others, including tubule injury following AKI. SIRT5 plays key roles in fatty acid oxidation which is a major energy source for the tubules of the kidney. Knocking out SIRT5 in mouse models has led us to theorize two processes that may be driving a protective phenotype in AKI,” says Dr. Sims-Lucas.

SIRT5 interacts with SIRT1 and 3, both of which are known to be protective sirtuins. Knocking out SIRT5, according to Dr. Sims-Lucas, may release SIRT1 and 3 from a competitive inhibition. “In the models, we see this upregulation of SIRT1 and 3 driving a protective phenotype such that the animals are not very susceptible to AKI.”

The second hypothesis is that the creation of large amounts of reactive oxygen species as a consequence of fatty acid oxidation, coupled with a hypoxic state or degree of hypoxia in an AKI, is detrimental to the tubule cells. “SIRT5 is thought to be largely a mitochondrial sirtuin, and it causes post-translational modifications, essentially cleaving off succinyl groups. What we believe is these models have accumulation of the post-translational modifications, which essentially then shunt fatty acid oxidation, to another organelle called the peroxisome. These peroxisomes then run fatty acid oxidation and we do not see as much reactive oxygen species production. This leads to our secondary mechanism of why we don’t see as much injury in these animals. This is an exciting direction to study, these positive regulators of kidney injury. There are ways that we could potentially pharmacologically target these pathways and in the future test that in humans,” says Dr. Sims-Lucas.

Kidney Precision Medicine Initiative

Dr. Sims-Lucas is part of the University of Pittsburgh team, led by primary investigator John Kellum, MD, professor of Critical Care Medicine and director of the Center for Critical Care Nephrology, working on the NIDDK’s Kidney Precision Medicine Project. This large scale, multi-institutional collaboration is designed to find new therapies and interventions to treat both acute kidney injury and chronic kidney disease. The University of Pittsburgh is one of the recruitment sites that will be collecting biopsies from AKI patients to be used in the creation of a biobank and molecular atlas of AKI to elucidate the mechanisms and phenotypes of AKI, and to identify potential novel treatment approaches.

The University of Pittsburgh’s grant for the project is called Phenotyping REnal Cases In Sepsis and surgery for Early Acute Kidney Injury (PReCISE AKI). The grant will facilitate the collection of biopsy and fluid (blood/urine) samples from patients with an early AKI and from those with more established cases to understand the specificity of clinical phenotypes between these kinds of cases, and if there are any predictors of injury resolution or future risk of developing chronic kidney disease.

References and Further Reading

Kidney Derived Endothelial Progenitors Play a Critical Role During Kidney Injury. Funding Agency: National Institute of Diabetes and Digestive and Kidney Diseases. Project Number: 5R03DK110503-02. Primary Investigator: Sunder Sims-Lucas.

Phenotyping REnal Cases In Sepsis and surgery for Early Acute Kidney Injury (PReCISE AKI). Funding Agency: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Project Number: 1UG3DK114861-01. Primary Investigators: John Kellum, Paul Palevesky, Matthew Rosengart.

Maringer K, Sims-Lucas S. The Multifaceted Role of the Renal Microvasculature During Acute Kidney Injury. Pediatr Nephrol. 2016; 31(8): 1231-1240.
Hemker SL, Sims-Lucas S, Ho J. Role of Hypoxia During Nephrogenesis. Pediatr Nephrol. 2016; 31(10): 1571-1577.

Mukherjee E, Maringer K, Papke BE, Schaefer C, Kramann R, Ho J, Humphreys BD, Bates C, Sims-Lucas S. Endothelial Marker-Expressing Stromal Cells Are Critical for Kidney Formation. Am J Physiol-Renal Physiol. 2017; 313(3): F611-F620.