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Pediatric Nephrology Researchers Obtain New R01 for AKI Research

June 17, 2020

UPMC Children’s Hospital of Pittsburgh Division of Pediatric Nephrology researchers Sunder Sims-Lucas, PhD, and Jacqueline Ho, MD, were awarded a four-year R01 grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), which is part of the National Institutes of Health (NIH).

Drs. Sims-Lucas and Ho’s new grant will fund research into how the microRNA (miRNA) cluster 17~92 may work to protect against the renal damage that results from an acute kidney injury (AKI). Their study will probe the role of miR-17~92 and its ability to protect and possibly repair the renal microvasculature after AKI.

AKI affects a substantial portion of hospitalized patients (approximately 20%) and an even greater number of critically ill patients (~50%). At present, there are no treatments outside of supportive measures to halt or reverse an AKI and the damage it inflicts on the kidney. Once an individual suffers an AKI, they are at significant risk for both another AKI and the development of chronic kidney disease (CKD). Finding an effective treatment for AKI is of the utmost importance to blunt the short- and long-term morbidity and mortality associated with AKI and subsequent CKD.

Previous studies in the laboratories of Dr. Sims-Lucas and Dr. Ho have shown that several of the miRNAs in the 17~92 cluster (17; 18a; 19a/b; 20a; 92a) are required for the normal development and function of the kidney. However, little is currently known about how these miRNAs function in the renal microvasculature. Additionally, there are two other gaps in the scientific knowledge that need to be addressed in order to develop therapies targeted at the renal microvasculature. The first is a better understanding of the molecular mechanisms that drive endothelial repair after AKI; the second, whether it is possible to modulate the capacity of the renal microvasculature for repair after AKI.

Preliminary data from the researchers in a knockout model of AKI in mice where miR-17~92 is deleted in endothelial cells show a high susceptibility to ischemic-reperfusion injury. The researcher’s central hypothesis is that miR-17~92 promotes endothelial cell repair after an injury and protects against AKI. The thrust of the R01 grant will attempt to understand the requirement for endothelial miR-17~92 during renal injury and repair, and to determine whether miR-17~92 is sufficient by itself to protect against renal injury associated with AKI.

Further Reading

Previously published work from Dr. Sims-Lucas and Dr. Ho that informs their new R01 are listed below. More details and the full abstract of the new grant can be found on the NIH RePORTER website.

The Role of MIR-17~92 in Nephron Progenitors. 5R01DK103776-05. Principal Investigator: Jacqueline Ho, MD.

The Role of Sirtuin 5 in Acute Kidney Injury. 1R56DK121758-01. Principal Investigator: Sunder Sims-Lucas, PhD.

Chiba T, Peasley KD, Cargill KR, Maringer KV, Bharathi SS, Mukherjee E, Zhang Y, Holtz A, Basisty N, Yagobian SD, Schilling B, Goetzman ES, Sims-Lucas S. Sirtuin 5 Regulates Proximal Tubule Fatty Acid Oxidation to Protect Against AKI. J Am Soc Nephrol. 2019 Dec; 30(12): 2384-2398.

Hemker SL, Cerqueira DM, Bodnar AJ, Cargill KR, Clugston A, Anslow MJ, Sims-Lucas S, Kostka D, Ho J. Deletion of Hypoxia-Responsive microRNA-210 Results in a Sex-Specific Decrease in Nephron Number. FASEB J. 2020 Mar 5. doi: 10.1096/fj.201902767R. [Epub ahead of print]

Phua YL, Chen KH, Hemker SL, Marrone AK, Bodnar AJ, Liu X, Clugston A, Kostka D, Butterworth MB, Ho J. Loss of miR-17~92 Results in Dysregulation of Cftr in Nephron Progenitors. Am J Physiol Renal Physiol. 2019 May 1; 316(5): F993-F1005.

Marrone AK, Stolz DB, Bastacky SI, Kostka D, Bodnar AJ, Ho J. MicroRNA-17~92 Is Required for Nephrogenesis and Renal Function. J Am Soc Nephrol. 2014 Jul; 25(7): 1440-1452

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