Cellular miscommunication may be root of kidney disease – Sanford Health News

Recent studies led by Sanford Research scientist Kamesh Surendran, Ph.D., reveal how cell to cell communication between cell types in the developing and adult kidney collecting ducts ensures the water reabsorption capacity.

A critical function of the kidney is water reabsorption, which is carried out in a highly regulated manner. In rare instances children are born with kidneys that do not reabsorb water adequately and may suffer from repeated episodes of dehydration resulting in stunted growth. Additionally, medications such as lithium, prescribed as a therapy for bipolar disorders, as a side-effect disable the kidneys water reabsorption capacity even in adults.

The Surendran Lab is focused on understanding the underlying mechanisms that determine the different cells that make up kidney collecting ducts. They recently published an article describing their work in the research journal Developmental Biology.

The different cell types of the kidney collecting ducts perform unique functions of the kidneys like regulation of water, electrolytes and pH homeostasis. When the kidney collecting ducts malfunction, it can lead to renal disease.

Findings from this study on mice, according to Dr. Surendran, could provide more information on genetic mutations that alter collecting duct cell functions and subsequently identify new human therapy options for diseases in these cells. Additionally, a better understanding of how these cells are made and maintained is essential for generating kidneys from patient-derived adult stem cells.

About 10 percent of U.S. adults, or more than 20 million people, have some degree of chronic kidney disease, the Centers for Disease Control and Prevention reports. According to Johns Hopkins University, around 1 in 500 children are born with abnormally developed kidneys due to genetic defects, which can lead to end-stage kidney disease.

Dr. Surendran sat down to talk with Sanford Health News about his history with Sanford Research and his latest work.

When it was time for me to move on from my post-doctoral training in Dr. Raphael Kopans lab at Washington University in St. Louis, Sanford Research was recruiting faculty to set up independent research programs with a focus on rare diseases. During my post-doctoral training I had stumbled on to a mouse model of the kidney disease that occurs in Alagille syndrome, a rare disease.

Professionally, I wished to set up a research program focused on how the kidney develops in order to understand and prevent what goes wrong in children born with kidney defects. Sanford Research appeared to be a great fit.

Personally, it was time for my family to move to a neighborhood with better schools as my daughter was almost ready to start kindergarten. The public school system in Sioux Falls is a blessing.

My graduate studies looking at kidney repair and regeneration made me realize that we dont really understand how the different cell types of the kidney develop. This led me to focus on understanding the genes and signals critical for normal kidney development during my post-doctoral training.

This paper on Foxi1 is the third one from my lab in a series on the topic of kidney collecting duct cell type differentiation and maintenance which we study using mouse models. The kidney collecting ducts form a branched tree-like tubular network that connects all the nephrons to the ureter and is made of two categories of cell types. Whereas we know quite a bit about the genes that regulate growth and branching of the collecting duct, we know far less about how the cells of the collecting ducts diversify and remain different to perform different specialized functions.

We previously used a novel tool which we refer to as principal cell lineage tracing mice, to prove that mature principal cells directly convert to intercalated cells, following inhibition of Notch signaling that are normally activated in principal cells by ligands expressed on neighboring intercalated cells. Interestingly, lithium treatment which is used to treat bipolar disorders also triggers principal-to-intercalated cell conversion. Patients treated with lithium tend to produce more dilute urine and develop a condition referred to as acquired nephrogenic diabetes insipidus. Since principal cells are important for water absorption to ensure sufficient hydration, this principal-to-intercalated-cell-type conversion may be part of the underlying cause of lithiums side-effect on the kidney.

In this recent paper we have identified how Notch signaling promotes principal cell fate selection during kidney development and in the process identified one way to rescue the principal cell deficiency and the urine concentrating deficiency in mice with reduced Notch signaling in the kidney collecting ducts. It remains to be determined if the kidney side-effects of lithium can be rescued by a similar mechanism.

The principal-to-intercalated-cell-type conversion in adult kidneys is a novel, unexpected finding from our previous study. We are looking into whether this cell type conversion is part of the mechanisms by which the kidney remodels its cell types in order to adapt to dietary changes such as excessive salt intake or an extremely low potassium diet. We are also examining whether certain medications prescribed to counter hypertension involve activation of Notch pathway and cell type conversion. Hence, understanding the mechanism by which Notch signal maintains the principal cells could open new ways to regulate and maintain kidney functions.

Many of the figures in this paper include confocal images which were made possible by the histology and imaging cores. Additionally, we made use of the mouse facility and metabolic cages to study the urine concentrating capacity of the mice. The ongoing work on this project is making use of the functional genomics and bioinformatics core to identify the direct targets of Hes1, and the biochemistry core to identify hes1 interacting proteins. The multitude of core facilities at Sanford Research strengthen our studies.

Malini Mukherjee, who was a post-doc in my lab and is now part of the Functional Genomics and Bioinformatics core, got to present these findings at the annual, internationally attended American Society of Nephrology (ASN) conference. It was exciting to have her abstract on this paper selected for an oral presentation at the end of 2018, which is an accomplishment in itself. Subsequently, I got invited to present a seminar on kidney collecting duct cell type differentiation and maintenance at the 2019 ASN conference. The quality and novelty of our published work has certainly been recognized within the kidney development field. What was pleasing for me is that a prominent kidney physiology researcher attended the talk and appreciated our work. This is important as our research is moving from development to maintenance which is the realm of renal physiologists.

Personally, it is fascinating to see that nature works in ways that is only limited by our imagination. Although Ive understood that mature cell types are actively maintained in a mature state, and had proposed to test if Notch signaling is required for principal cell maintenance, I had not anticipated that mature kidney epithelial cell types can switch directly from one fate to another. To top that, it may turn out that this cell type conversion is part of the way in which the kidney adapts to certain diets to perform its normal functions.

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Cellular miscommunication may be root of kidney disease - Sanford Health News