Massive single-cell survey of kidney cell types reveals new paths to disease
PHILADELPHIA – The kidney is a highly complex organ – far beyond a simple filter. Its function requires intricate interactions between many highly specialized cell types to extract waste, balances body fluids, form urine, regulate blood pressure, and secrete hormones. New research from a team in the Perelman School of Medicine at the University of Pennsylvania shines a light on specific cell types that drive normal or diseased kidney function at the molecular level.
By sequencing the RNA from 57,979 cells from healthy mouse kidneys, the team found that mutations in genes that have similar characteristics are expressed in a single unique differentiated cell type. The study, led by Katalin Susztak, MD, PhD, a professor of Renal-Electrolyte and Hypertension and Genetics, also identified three novel cell populations, along with all previously described kidney cell types. They published their findings online this week in Science.
"The work provides unprecedented insight into kidney physiology and disease," Susztak said. "Each cell in the kidney seems to have a unique non-redundant function, and dysfunction of specific cell types present with specific symptoms in people. Using our approach we are starting to understand how kidney disease develops at the level of a single cell." The overall prevalence of chronic kidney disease in America is about 14 percent, according to the National Institute of Diabetes and Digestive and Kidney Diseases.
The Penn team unexpectedly found that what they thought were two irreversibly differentiated and distinct cell types in the kidney could convert to each other. The interconversion was also observed in kidney disease mouse models. They analyzed a large cohort of human patient samples from the human kidney biobank managed by Susztak and found that the interconversion might also occur in patients with kidney disease and likely contributes to a condition when the kidneys cannot remove enough acid from the body.
"Knowledge from our survey will enhance our understanding of the roles that different cell types play during normal kidney functioning and dynamic changes occurring during disease development," Susztak said. "When combined with existing knowledge, this study provides a new roadmap for future studies to identify the underlying causes of chronic kidney disease. A change in the basic identity of the cells, means that kidney disease 'reprograms' the kidney. Our goal is to find methods to undo this reprograming."
Coauthors include Jihwan Park, a postdoctoral fellow supported by the American Diabetes Association fellowship, Rojesh Shrestra and Mingyo Li from Penn and Jonathan Barasch from Columbia University. Work in Susztak's lab is supported by the National Institutes of Health (R01 DK076077, R01 DK087635, DP3 DK108220). Research in Barasch's lab has been supported by NIH (1U54DK104309-01, 2R01DK073462, DK-16-026).
Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $7.8 billion enterprise.
The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $405 million awarded in the 2017 fiscal year.
The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center — which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report — Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; Penn Wissahickon Hospice; and Pennsylvania Hospital – the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine, and Princeton House Behavioral Health, a leading provider of highly skilled and compassionate behavioral healthcare.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2017, Penn Medicine provided $500 million to benefit our community.