Balancing a Fluid Situation
Sometimes, when scientists want to simplify anatomy, they refer to the human body as a “giant bag of mostly water.” In many ways, the human body is a complex collection of fluids that must be carefully balanced so it can perform internal processes and remain healthy. To maintain the balance of fluids, nutrients, and other molecules within the body, humans rely on their kidneys to regulate filtration, absorption and blood pressure. While scientists know the general structure and inner workings of the kidney at the level of tissues, the processes at cellular, or even smaller, levels remain a mystery.
To get a closer look, NIH-funded scientists created a 3D map of kidney nerves and vascular components at an unprecedented scale and detail, even down to individual cells. Researchers used the map to identify structures connected by nerve cells that coordinate function across the kidney and fully develop by adulthood. These structures are disrupted in kidney diseases. Understanding kidney structure and function at this level of detail may provide new clues toward future treatments for conditions that affect kidney development or cause kidney-related disease.
As part of solving that mystery, the NIH-funded researchers—Dr. Sanjay Jain of Washington University at St. Louis, Dr. Gloria Pryhuber of the University of Rochester Medical Center, and members of their labs—used cutting-edge methods to examine samples from human patients of different ages to gain new insights about changes in kidney structure and function across the lifespan. This work is part of the NIH Common Fund-supported Human BioMolecular Atlas Program (HuBMAP), which is building an atlas of 3D maps from many organs across the body.
“This finding exemplifies how development of innovative techniques and methods can lead to greater discoveries and treatments for human health,” said Dr. Griffin Rodgers, director of NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), one of the NIH institutes helping to manage HuBMAP.
To create the 3D map, researchers used special illuminated molecular tags that can recognize specific components inside kidney cells. The tags bind to those components, and then their position can be noted under a special type of microscope. This technique allowed researchers to identify tagged components and use them as signposts to navigate inside the kidney at the level of individual cells and even smaller. This technique is a major breakthrough; most studies of kidney structure to date are two-dimensional and lack this new level of detail.
Scientists have long known that kidneys are composed of millions of capsules and tubules, which together form a functional unit called the “nephron.” Nephrons filter blood inside the kidney to keep the necessary molecules and remove the harmful ones.
At the opening of each nephron, there is a sieve-like network of blood vessels called the “glomerulus.” The researchers found that glomeruli organize themselves into communities, connected by a network of nerve cells. Most importantly, the researchers found several patterns of connected communities they named “mother-gloms.” The researchers believe the mother-gloms sense and then relay signals to other neighboring nephrons. These control centers appear to help synchronize the responses to changes in the fluid balance of the body, coordinating biological functions and decreasing the burden on individual nephrons.
The researchers also studied how kidney structure changes over time from infants to older adults. In infant kidneys, they found the nerve network of the mother-gloms had not yet matured; the structures were more tightly packed and less interconnected. As the kidneys grew, connections and organization among the glomeruli increased until adulthood.
In older adults, the researchers saw that many glomeruli had shrunk or changed in shape. There were also notable changes in kidney structure in patients with kidney disease or diabetes, including changes to nerve connections among glomeruli and even fewer nerves in diabetes patients.
This work defines how the kidney’s structure allows a coordinated response across the organ and how disruptions in this system can lead to disease. It also reveals how the kidneys change over a person’s lifetime, offering insights into managing kidney health and preventing related diseases.
HuBMAP is managed by NIH’s Office of the Director; NIH’s National Heart, Lung, and Blood Institute (NHLBI); NIH’s National Institute of Biomedical Imaging and Bioengineering (NIBIB) and NIDDK.