Researching the Origins and Drivers of Kidney Development and Chronic Kidney Disease
January 7, 2019
While much is known about the origins and processes of kidney development, there remain gaps in our understanding of the basic science and molecular mechanisms of kidney formation — normal and abnormal. The same can be said for various kidney pathologies and the causes of renal failure and chronic kidney disease. Unfortunately, there also exists a very limited arsenal of therapies to slow the progressive loss of renal function in individuals with chronic kidney disease.
The laboratory of Jacqueline Ho, MD, assistant professor and director of the Pediatric Nephrology Fellowship Program in the Division of Pediatric Nephrology, is pursuing new lines of research into the role of microRNAs (miRNAs) and how they may regulate kidney development and disease processes. Dr. Ho’s lab has also begun basic science studies on how certain in utero exposures, specifically maternal diabetes and hypoxia, may affect kidney development and how this might impact the risk of chronic kidney disease in the child.
MicroRNAs and Kidney and Nephron Formation
As Dr. Ho explains, approximately a third of the cases of chronic kidney disease (CKD) they see in the Division are attributable to congenital anomalies of the kidney and urinary tract, with renal dysplasia/hypoplasia being the leading cause of renal failure. There is also a wide variation from individual to individual in the quantity of nephrons in their kidneys. Individuals with fewer nephrons may be predisposed to CKD because of a relative lack of renal reserve in the face of various disease processes, acute injuries, and perhaps even the aging process. “The nephron has and needs a very complicated, three-dimensional structure to work appropriately.
“How well an individual’s nephrons are made, and how many they have at birth, are likely big influences on a predisposition,” says Dr. Ho. “To better understand both the formation and quantities of nephron development, we are studying the role of small molecules called microRNAs in transgenic mouse models,” says Dr. Ho.
miRNAs are small, non-coding molecules that function in the regulation of posttranscription gene expression, and are known to be important in many biological and developmental processes of organs and organ systems. Dr. Ho and her colleagues are broadly interested in how miRNAs work to influence kidney and nephron development (both formation and quantity), and their implication in disease processes. In terms of their role in kidney development, miRNA research is really in its infancy, but the literature is growing. So, too, is the goal to develop novel regenerative therapies through the propagation and manipulation of nephron progenitors.
Past work by Dr. Ho and colleagues uncovered the role of a cluster of miRNAs — miR-17~92 — in kidney development.1“In this experiment, the deletion of miR-17~92 in the animal model showed this miRNA cluster to be important in renal and nephron development. We saw a reduced capacity, or number of nephrons developed, and postnatally the animal models showed signs of renal disease,” says Dr. Ho.
miRNAs and Disease Process
Another major area of focus of Dr. Ho’s research, one that is beginning to take on more prominence, is a better understanding of miRNAs in the context of specific disease processes. This work is related to her past studies of miR-17~92. “We are also looking at models of acute kidney injury with our division, colleague Sunder Sims-Lucas, PhD, in relation to microRNAs. Clearly, we believe this is an important field of study, and our group is moving more along these lines of research to study how microRNAs may regulate disease processes.”
Kidney Development, CKD, and In Utero Exposure to Diabetes and Hypoxia
While microRNAs are a primary focus of research for Dr. Ho, new, ongoing studies in her laboratory are investigating how certain in utero exposures may affect kidney development (nephrogenesis) or predispose one to future disease.
One such line of investigation, in collaboration with Dr. Sims-Lucas’ laboratory, is delving into how and why children born to mothers with diabetes predisposes them to a higher risk of congenital anomalies of the kidney and urinary tract. “We don’t yet know if the exposure to high glucose environments is causative. It may be a cluster of metabolic events that results from the diabetic milieu that is important for the development of pathology. It’s an intriguing question, and one we hope to provide some answers to,” says Dr. Ho.
Exposure to hypoxia in utero often leads to kidney malformation. The reasons are not specifically known at this time. However, an investigator in Dr. Ho’s lab, Shelby Hemker, is studying the role of microRNA-210, which is induced in hypoxia, to better understand how this may impact nephron development and quantity.
Dr. Ho and colleagues from the Division of Pediatric Nephrology have recentlymbegun working with the University of Pittsburgh Center for Biologic Imaging (CBI) onimaging studies of the kidney.2 The novel technology they have developed allows for then imaging of whole organs and other structures at the cellular level, achieving heretofore unheard of levels of resolution and detail. “The technology the CBI has worked to develop effectively allows us to image the entire kidney at the cellular level. We can actually count the number of nephrons in the kidney and see other structures in amazing detail and clarity,” says Dr. Ho. More about the CBI and their imaging technology can be found at Pittmed.health.pitt.edu/story/voyages-fantastic.
References and Further Reading
1 Marrone AK, Stolz DB, Bastacky SI, Kostka D, Bodnar AJ, Ho J. miR-17~92 Is Required for Nephrogenesis and Renal Function. J Am Soc Neph. 2014; 25(7): 1440-1452. PMID 24511118.
2 Pittmed.health.pitt.edu/story/voyages-fantastic This article discusses in detail the University of Pittsburgh’s Center for Biologic Imaging and its novel 3D scanning technology able to image organs and anatomic structures with high resolution at the cellular level, the only one of its kind in the United States.
3 Phua YL, Chu JYS, Marrone AK, Bodnar AJ, Sims-Lucas S, Ho J. Renal Stromal miRNAs Are Required for Normal Nephrogenesis and Glomerular Mesangial Survival. Physiol Reports. 2015 Oct; 3(10); pii: e12537. doi: 10.14814/ phy2.12537. PMID 26438731.
4 Liu X, Edinger RS, Klemens CA, Phua YL, Bodnar AJ, LaFramboise WA, Ho J, Butterworth MB. A microRNA Cluster miR-23~24~27 Is Upregulated by Aldosterone in the Distal Kidney Nephron Where It Alters Sodium Transport. J Cell Physiol. 2016 Sept 16, published online. doi: 10.1002/ jcp.25599. PMID27636893.
5 Cerqueira DM, Bodnar AJ, Phua YL, Freer R, Hemker SL, Walensky LD, Hukriede NA, Ho J. Bim Gene Dosage Is Critical in Modulating Nephron Progenitor Survival in the Absence of microRNAs During Kidney Development. FASEB J. 2017 Aug; 31(8): 3540-3554. PMID28446592.
