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New Kidney Mapping Could Lead to Health Gold

Through studies in mice, researchers have gained fundamental new insights into kidney development and organization and how they differ between males and females—all of which could aid research efforts to battle human kidney diseases. Humans and other mammals possess two kidneys, which are organs that filter waste and toxins from the blood, regulate salt and blood pressure, and produce hormones that regulate other critical functions in the body. Each kidney is a complex structure containing thousands of essential functional units called nephrons arranged in a radial, interconnected pattern resembling the dense crown of branches on a very old oak tree; together, these units filter the blood repeatedly each day and ultimately rid the body of waste and toxins in urine while retaining essential components, such as proteins and glucose. Millions of people suffer from kidney disease and kidney failure due to a variety of causes, and researchers have also observed differences between women and men in protection from kidney injury. A better understanding of the cellular functions and development of the kidneys is key to finding ways to reverse, avoid, or fix such injuries and disease.

In a major advance, researchers used a painstaking method called single cell RNA sequencing to identify genes that are expressed (turned on or off) in adult male and female mouse kidney cells. To organize the results, they divvyed each kidney into three zones corresponding to its outer, middle, and innermost anatomical regions prior to extracting cells, and assigned representative cells from each zone into “clusters” based upon gene expression patterns. They then combined those results with the results of imaging studies that allowed them to visualize, trace, and compare the development and localization of different mouse kidney tissues and structures over time from the embryonic stage to maturity. Together, these experiments yielded a wealth of information, such as details on how nephrons differ in the outer versus middle parts of the kidney, the cellular origins of different structures and junction points of nephrons, and intriguing sex differences in nephron gene expression that provide new targets for study. For example, evidence suggests that female mice and humans are resistant to a type of kidney injury that primarily affects a section of the nephron called the proximal tubule. The researchers found that the expression of genes involved in transport of small molecules and metabolism of drugs, cholesterol, and hormones—all functions of the proximal tubule—differed between female and male mice. Interestingly, in a second recent study, another team of researchers also found differences in gene expression between female and male mice when they examined the same section of the nephron post-injury, further bolstering the importance of this region—and these genes—as study targets in understanding kidney disease and kidney protection.

Researchers from the first study have used their results to generate a web-searchable, annotated anatomical database for use by the scientific community. Although there are limitations on some of the data—for example, some kidney cell types were underrepresented in the study because they did not survive the experimental procedures as well—these results from mice can serve as a guidepost in similar mapping of human kidney. This research also points to potential explanations for both general vulnerabilities and sex-specific protective factors in kidney injury and ultimately a better understanding of kidney diseases and kidney failure—and thus new ideas for therapies.

Ransick A, Lindström NO, Liu J,...McMahon AP. Single-cell profiling reveals sex, lineage, and regional diversity in the mouse kidney. Dev Cell 51: 399-413.e7, 2019.

Wu H, Lai CF, Chang-Panesso M, and Humphreys BD. Proximal tubule translational profiling during kidney fibrosis reveals proinflammatory and long noncoding RNA expression patterns with sexual dimorphism. J Am Soc Nephrol 31: 23-38, 2020.