This Science Short, written by Lauren Elizabeth Lee, summarizes the findings of: Lee, L.E., Doke, T., Mukhi, D., & Susztak, K. (2024). The key role of altered tubule cell lipid metabolism in kidney disease development. Kidney International 106(1). https://doi.org/10.1016/j.kint.2024.02.025.
What is chronic kidney disease (CKD)?
1 in 7 US adults suffer from Chronic Kidney Disease (CKD), a disease where the kidneys become damaged and stop functioning properly. The kidneys are vital organs which filter all the blood in the body. They reabsorb important minerals, electrolytes, and metabolites (small molecules involved in metabolism), and remove toxins and excess fluid through urine. However, in CKD, the kidneys struggle to perform these functions, leading to a buildup of toxins, waste, and excess fluid in the body. CKD can also contribute to other chronic health issues such as heart disease and diabetes.
How much energy do the kidneys need to function?
The kidneys filter around 1800 liters of blood a day. Since the average adult has 5 liters of blood, this means the kidneys filter all the body’s blood over 300 times daily! As such, the kidneys need a lot of energy. The proximal tubule is the part of the kidney that does the majority of thiswhich is responsible for work in reabsorbing what the body needs and discarding what is not needed. In a healthy kidney, the proximal tubule cells primarily use fatty acid oxidation, where fats are broken down to produce energy. Fatty acid oxidation is the most efficient way of generating energy for the cell, compared to using carbohydrates (sugars) or protein.
What happens when kidney fat metabolism stops working properly?
In diseased kidneys, fat metabolism changes. Proximal tubule cells exhibit fatty acid oxidation defects and instead increase lipid (fat) storage in the cell. This leads to lipid droplet accumulation in proximal tubules cells, which can interact with and cause damage to other parts of the cell, causing the proximal tubule cell to function improperly. This ultimately worsens kidney disease. Using both human CKD kidney samples and rodent CKD models, we used single cell gene expression analysis and bulk RNA gene analysis (techniques that measure changes in gene activity in single cells and in a large population of cells, respectively). We showed decreased activity of genes for fatty acid oxidation and increased activity of genes for lipid storage in the kidney. Also, we discovered both humans with CKD and rodent CKD models have similar changes in gene activity responsible for a process called de novo lipogenesis, where the kidney can make more fat from carbohydrates.
What are potential treatments for targeting defective fat metabolism in CKD?
Developing drugs that target important genes regulating fatty acid oxidation may help restore proper fat metabolism function. Another viable therapeutic approach could be to limit lipid storage, by preventing either the fat buildup or the creation of new lipids. Interestingly, not all types of lipids that accumulate in the kidney are toxic to the cell. Understanding why some lipids are neutral or beneficial on proximal tubule cells can help guide drug development.
What do we need to do next?
1. Research: We need to better understand how the complex balance of fat breakdown, storage, and creation in kidney proximal tubule cells contribute to CKD. Advances in genetic sequencing techniques and spatial metabolomics (the ability to see changes of metabolites in a specific region of an organ) can yield deeper insights into gene expression and metabolite levels in kidney disease.
2. Policy: Prioritizing funding for research on metabolism in CKD and other diseases is crucial. Local and federal agencies should also invest in evidence-based nutritional education and awareness. Medical nutrition therapy provided by registered dietitians has been shown to slow kidney disease progression. Including telehealth reimbursements for registered dietitians providing medical nutrition therapy in Medicaid- and Medicare-covered services plans can also improve access and equity, especially for low-income individuals disproportionally affected by CKD.
Acknowledgements
This work was supported by the National Institutes of Health grant National Institute of Diabetes and Digestive and Kidney Diseases (NIDD) T32DK007314 (to LEL). Figures created with BioRender.com.
Lauren Elizabeth Lee is a 3rd year PhD candidate in Cell and Molecular Biology (concentration: Cell Biology, Physiology, and Metabolism) at the Perelman School of Medicine at the University of Pennsylvania. Her thesis research focuses on understanding how metabolism drives both kidney disease and heart disease in cardiovascular-kidney-metabolic syndrome (the combination of obesity/diabetes with kidney and heart diseases) under the mentorship of Dr. Zoltan Arany in the Penn Cardiovascular Institute. She is supplementing her training with both the Penn Graduate Training in Medical Science and the Penn Carey Law certificates. Additionally, she is a policy intern at the American Society of Nephrology, where she draws from both her clinical and research experiences to advocate for kidney health initiatives and policies at the federal and state level.
Prior to Penn, Lauren worked in a kidney inflammation lab at UT Southwestern Medical Center in Dallas, Texas and completed her undergraduate studies in Sports Medicine and Applied Music-Cello Performance at Pepperdine University in Malibu, CA.