To know the kidney is to know its cells, all of them, every type and subtype, and how they sustain health or contribute to disease. Although many kinds of kidney cells have been distinguished based on their function, anatomical location, or small numbers of marker genes, the kidney is still perceived but vaguely, in the sense that differences between existing cell-based classification schemes have yet to be fully resolved. To bring the kidney into sharper focus, a team of scientists at the University of Pennsylvania School of Medicine looked at it through a particularly powerful lens: single-cell transcriptomics.

The team used single-cell transcriptomics, a means of examining gene-expression patterns in thousands of individual cells in a single experiment, to characterize more than 57,000 cells from healthy mouse kidneys. This work allowed the team to trace the expression of genes related to proteinuria, blood pressure regulation, chronic kidney disease (CKD), nephrolithiasis, and renal tubular acidosis to specific cell types. The team also identified a new type of cell that transitions between two different states. When this transition goes awry, the team discovered, adverse consequences could include metabolic acidosis.

Details of the single-cell analysis, appeared April 5 in the journal Science, in an article entitled, “Single-cell transcriptomics of the mouse kidney reveals potential cellular targets of kidney disease.” Besides describing results from mouse studies, the article presents an analysis of a large cohort of human patient samples.

“Based on gene-expression patterns, we infer that inherited kidney diseases that arise from distinct genetic mutations but share the same phenotypic manifestation originate from the same cell differentiated type,” the article’s authors wrote. “We also found that the kidney collecting duct in adult mice generates a spectrum of cell types via a newly identified transitional cell.”

The article emphasizes that single-cell analyses can enhance our understanding of normal kidney function and disease development. Such analyses provide investigators the resolution they need to characterize the intricate interactions between the kidney’s many highly specialized cell types to extract waste, balances body fluids, form urine, regulate blood pressure, and secrete hormones.

“The work provides unprecedented insight into kidney physiology and disease,” said Katalin Susztak, M.D., Ph.D., the Science article’s senior author and a professor of Renal-Electrolyte and Hypertension and Genetics. “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%, according to the National Institute of Diabetes and Digestive and Kidney Diseases.

When they looked more deeply into the transitioning cell types, Dr. Susztak and colleagues found that the kidney collecting duct in adult mice generates a spectrum of cell types. “Computational cell trajectory analysis and in vivo lineage tracing revealed that intercalated cells and principal cells undergo transitions mediated by the Notch signaling pathway,” the scientists indicated. “In mouse and human kidney disease, these transitions were shifted toward a principal cell fate and were associated with metabolic acidosis.”

“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,” Dr. Susztak concluded. “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.”

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