A clue to the causes of kidney disease: It’s in your cells – Sanford Health News

More than than 30% of Americans are at risk of kidney disease, and nearly 20% of all Medicare spending is for kidney disease in patients 65 and older. Yet there is still much not known about the development of kidney disease.

Dr. Indra Chandrasekarand her team of researchers recently published an article in the biomedical research journal JCI Insight, highlighting the impact of key cellular processes on kidney health and function. The discovery allows researchers to better understand how kidney disease forms.

The kidney carries out many functions that are necessary to maintain overall health. As a result, any disruption to those functions can cause kidney disease. To find where kidney disease starts, the Chandrasekar Lab chose to study functions at the cellular level.

When researchers turned off the genes for certain proteins in mice at 4 weeks of age, the mice began to exhibit worsening dilation of the kidney tubules accompanied by eventual kidney degeneration and cyst formation by 12 weeks of age. Along with these structural changes came functional changes within the kidneys, including more acidic urine, excretion of protein and salts, and inflammation as the disease progressed.

This work highlights a new and major role for the proteins, called nonmuscle myosin II (NM2A and NM2B), in maintaining the health and function of the kidneys. This finding provides key knowledge to the kidney disease field as the pursuit of a cure continues to drive the valuable work being performed at Sanford Research.

Dr. Indra Chandrasekar sat down to talk with Sanford Health News about her history with Sanford Research and her recent work.

The myosin motor family, and NM2 proteins in particular, has been studied for over five decades. NM2s role in cell migration, adhesion and cell division has been carefully examined in vitro as well as with organismal and developmental context. Work in the Chandrasekar Lab is focused on understanding the physiological and cell-type specific role for NM2 mediated cellular transport mechanisms using mouse kidney as a model. Turning off the NM2 genes in adult mouse kidney tubular epithelial cells demonstrates that NM2 function is critical for the transport of two important proteins within kidney. These two proteins are called uromodulin (UMOD) and sodium, potassium, chloride cotransporter (NKCC2), that are essential for maintaining electrolyte balance and blood pressure in our body.

Mutations in UMOD and NKCC2 genes in humans lead to kidney disease. Membrane-associated NKCC2 has been the target of several blood-pressure regulating medicines currently on the market. Therefore, it is critical to further explore and understand how NM2 proteins regulate UMOD and NKCC2 transport and function in within the kidney cells.

Personally, this published work has been our teams mission for the past several years. As the Nobel-prize winning neurobiologist Rita Levi-Montalcini once said, I dont believe there would be any science at all without intuition. The findings described in this manuscript began as an intuition that stemmed from my postdoctoral work. I am very happy with how it turned out and extremely grateful for our teams hard work.

As a cell biologist, I am fascinated by the molecular and cellular complexity of the kidney. Considering that mutations in MYH9 (NM2A protein) in humans are linked to kidney disease, and that the epithelial cells of the kidney are great models to study cellular transport pathways, it was an easy organ of choice. Moreover, the availability of excellent mouse genetic tools to perform cell-type specific, inducible and conditional gene inactivation in the kidney is also a positive.

The impact of our published work is twofold:

I worked at a local clinical laboratory in town during the first year of my undergraduate biochemistry program. My job was to prepare, stain and perform microscopic analysis of peripheral blood smears from patient blood. I was fascinated by the cellular morphology, staining characteristics and intracellular organelles present in the varying types of blood cells. I wanted to understand how different cell types in our body function and what happens when they do not perform their assigned jobs. This interest led me to Dr. Brigitte M. Jockushs laboratory in Germany for my Graduate work. Professor Jockusch is a well-respected expert in the field of cytoskeletal research and cell biology. Being in her lab was a great privilege. I continued my training with prominent cell biologists such as Dr. John A. Cooper and Dr. Paul C. Bridgman at the Washington University in St. Louis.

During my training as a post-doctoral scientist at Washington University in St. Louis, I had determined a new, critical role for nonmuscle myosin 2 (NM2) motors in processes by which proteins are transported into and within cells. At Sanford Research, I got the opportunity to follow on my previous findings and to start an independent research program to understand the molecular mechanisms underlying kidney tubular transport defects to human kidney diseases. The excellent, state-of-the-art facilities to conduct basic and clinical research at Sanford Research has led us to publish a manuscript of high impact that reports that the loss of NM2 proteins in adult kidney epithelium results in progressive chronic kidney disease.

I enjoy thinking about new ideas and concepts and testing those using experiments in the lab to gain insights into cellular mechanisms. I love performing advanced microscopy experiments. However, the most enjoyment comes from passing along the valuable techniques and scientific concepts to future scientists who are trainees and let them excel in whatever they desire in their life.

Posted In Genetics, Health Care Heroes, Research

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A clue to the causes of kidney disease: It's in your cells - Sanford Health News