Research Finds Urinary Prostaglandin E2 is a Biomarker for Hyperfiltration Injury
Investigating Fluid Flow Shear Stress in Hyperfiltration-Mediated Kidney Injury and Nephrotic Syndrome in Children
Hyperfiltration is seen as the primary cause of early progression of chronic kidney disease (CKD) in children with congenital anomalies of the kidney and urinary tract (CAKUT). Tarak Srivastava, MD, Director of the Nephrology Research Laboratory at Children’s Mercy Kansas City and Professor of Pediatrics, University of Missouri-Kansas City School of Medicine, supported by R01 funding from the National Institutes of Health (NIH), is making important discoveries pertaining to CKD progression, with lab research focused on podocyte cell biology and its role in the pathophysiology and potential treatment of hyperfiltration injury.
His research also focuses on the role of innate immunity in idiopathic nephrotic syndrome in childhood, and in kidney development.
While research on these subjects transcends into the adult world, Dr. Srivastava is one of only a handful of nephrologists focused on identifying and mitigating the risk factors for chronic kidney disease in children.
Mitigating Risk Factors for Chronic Kidney Disease
Dr. Srivastava’s research has validated the importance of cyclooxygenase enzyme-2 (COX2), prostaglandin E2 (PGE2), and prostanoid receptor EP2 in the podocyte as a critical pathway that may play an important role in hyperfiltration-mediated injury.
To study this further, he was awarded a five-year R01 grant from the NIH to work on targeting prostanoid receptor EP2, one of the four PGE2 receptors, to mitigate hyperfiltration-mediated kidney injury to delay the progression of chronic kidney disease in children born with CAKUT.
Recently, his research has shown that elevated SNGFR results in increased fluid flow shear stress and increased expression of prostanoid receptor EP2 during early-stage CKD in animal models. He has now shown that urinary PGE2 excretion precedes overt microalbuminuria and is a biomarker for early hyperfiltration-induced injury in children born with a solitary functioning kidney. Supported by his NIH funding, Dr. Srivastava published this research in Prostaglandins & Other Lipid Mediators in February 2020.1
A second study, Upregulated Proteoglycan-related Signaling Pathways in Fluid Flow Shear Stress-treated (FFSS) Podocytes, was published in the American Journal of Renal Physiology in August 2020. In this study, Dr. Srivastava and his colleagues showed the importance of podocyte glycocalyx in response to FFSS, which builds on his previous work establishing the importance of COX2-PGE2-EP2 axis and Akt-GSK3β-β-catenin signaling downstream of prostanoid receptor EP2. This was based on cell and animal work on fluid flow shear stress.2,3,4 These studies allow us to develop potential therapeutic strategies to mitigate hyperfiltration-mediated injury.
And finally, in the original research article published in Frontiers in Physiology called Unilateral Nephrectomy Stimulates ERK and Is Associated with Enhanced Na Transport, the authors discuss the relevance of FFSS in tubular cells, resulting in activation of ERK signaling.5
Researching Development of Nephrotic Syndrome
Although primary nephrotic syndrome is a relatively rare condition, according to the NephCure Kidney International Foundation, it is responsible for 20% of kidney failure in children, making it an important research target.
Dr. Srivastava is well known for his expertise in idiopathic nephrotic syndrome as part of his clinical practice, which intersects with his laboratory research. He is recognized as a nephrotic syndrome specialist by NephCure, and he has studied the role of innate immunity in podocytes to better understand the mechanisms behind the development of nephrotic syndrome.
Dr. Srivastava is involved in clinical trials related to idiopathic nephrotic syndrome and is part of the National Institutes of Health multicenter studies, NEPTUNE, CureGN and FONT; American Heart Association (ECHO-NEPTUNE); and industry investigations (Abatacept, ATLANTIS, Duplex and DUET) as the Children’s Mercy site principal investigator.
Many of these trials are investigating therapies for children with treatment-resistant nephrotic syndrome. Children’s Mercy also participates in the Pediatric Nephrology Research Consortium, which provides Dr. Srivastava an opportunity to collaborate with other pediatric nephrologists around the country to participate in collaborative research.
Committed to Transformational Research
The Division of Pediatric Nephrology at Children’s Mercy is one of the most academically productive departments in the country, publishing 63 peer-reviewed manuscripts in 2020. Children’s Mercy physician-scientists are committed to leading transformational research, from bench to bedside, to create a world of well-being for all children with pediatric kidney disease.
To learn more about our research or to collaborate with us, contact Bradley Warady, MD, Division Director, Children’s Mercy Nephrology, at bwarady@cmh.edu.
Learn More About Pediatric Kidney Disease Research at Children's Mercy
Tarak Srivastava, MD, Director, Nephrology Research Laboratory at Children’s Mercy
(816) 234-3010
For consults, admissions or transport call: 1 (800) GO MERCY / 1 (800) 466-3729.
References:
Srivastava T, Ju W, Milne GL, Rezaiekhaligh MH, Staggs VS, Alon US, Sharma R, Zhou J, El-Meanawy A, McCarthy ET, Savin VJ, Sharma M. Urinary prostaglandin E2 is a biomarker of early adaptive hyperfiltration in solitary functioning kidney. Prostaglandins & Other Lipid Mediat. 2020 Feb;146:106403.
Srivastava T, Joshi T, Jiang Y, Heruth DP, Rezaiekhaligh MH, Novak J, Staggs VS, Alon US, Garola RE, El-Meanawy A, McCarthy ET, Zhou J, Boinpelly VC, Sharma R, Savin VJ, Sharma M. Upregulated proteoglycan-related signaling pathways in fluid flow shear stress-treated podocytes. Am J Physiol Renal Physiol. 2020;319(2):F312-F322.
Srivastava T, Dai H, Heruth DP, Alon US, Garola RE, Zhou J, Duncan RS, El-Meanawy A, McCarthy ET, Sharma R, Johnson ML, Savin VJ, Sharma M. Mechanotransduction signaling in podocytes from fluid flow shear stress. Am J Physiol Renal Physiol. 2018 Jan 1;314(1):F22-F34.
Srivastava T, Alon US, Cudmore PA, Tarakji B, Kats A, Garola RE, Duncan RS, McCarthy ET, Sharma R, Johnson ML, Bonewald LF, El-Meanawy A, Savin VJ, Sharma M. Cyclooxygenase-2, prostaglandin E2 and prostanoid receptor EP2 in fluid flow shear stress mediated injury in solitary kidney. Am J Physiol Renal Physiol. 2014;307(12):F1323-33.
Repetti R, Majumder N, Carneiro De Oliveira K, Meth J, Yangchen T, Sharma M, Srivastava T, Rohatgi R. Unilateral nephrectomy stimulates ERK and is associated with enhanced Na transport. Frontiers in Physiology. Feb. 3, 2021. https://doi.org/10.3389/fphys.2021.583453.
Children’s Mercy Kansas City is an independent, non-profit, 390-bed pediatric health system, providing over half a million patient encounters each year for children from across the country. Children’s Mercy is ranked by U.S. News & World Report in all ten specialties. We have received Magnet® recognition five times for excellence in nursing services. In affiliation with the University of Missouri-Kansas City, our faculty of nearly 800 pediatric specialists and researchers is actively involved in clinical care, pediatric research and educating the next generation of pediatricians and pediatric subspecialists. The Children’s Mercy Research Institute (CMRI) integrates research and clinical care with nationally recognized expertise in genomic medicine, precision therapeutics, population health, health care innovation and emerging infections. In 2021 the CMRI moved into a nine-story, 375,000-square-foot space emphasizing a translational approach to research in which clinicians and researchers work together to accelerate the pace of discovery that enhances care.