Research May Improve Targeted Treatments for Kidney-related Diseases

Inhibiting the lipid kinase VPS34 may improve the treatment of diseases such as diabetes and kidney cancer.

A new study shows that a lipid kinase is involved in adjusting endocytosis, nutrient transport, autophagy, and antiviral responses in proximal tubule cells in the kidney, which may lead to the development of targeted therapies for kidney-related diseases.

The study, led by Markus Rinschen from Aarhus Institute of Advanced Studies and the Department of Biomedicine at Aarhus University, noted that the kidney filters 180 liters of blood per day and retains nutrients through endocytosis and through active transport in the kidney cells. The study authors analyzed how the endocytosis process is regulated by the lipid kinase VPS34, which is involved in vesicular trafficking and endocytic sorting of membrane proteins. This process is not only critical for the body in obtaining the right nutrients, but also in blocking out harmful intruders, such as viruses, for example.

“Our primary goal in this study was to gather and organize novel knowledge of the fundamental processes of cell physiology. Although this is hypothesis-free, these comprehensive large-scale datasets can be central to understand medical problems. In this case, we ultimately improved targeted drug treatment for instance for kidney related diseases or infections,” Rinschen said in a press release. “Of course, more knowledge needs to be gathered before any conclusions regarding human relevance can be made.”

The study authors applied a new method they called “multiomics,” in which they combine multiple data sets to provide a comprehensive view of cell physiology. The hypothesis-free approach is able to quantify the functions of multiple transporters and enzymes.

“The lipid kinase VPS34 orchestrates autophagy, endocytosis, and metabolism and is implicated in cancer and metabolic disease. The proximal tubule in the kidney is a key metabolic organ that controls reabsorption of nutrients such as fatty acids, amino acids, sugars, and proteins,” the study authors wrote.

This analysis showed that a lack of lipid kinase in proximal tubule cells in a mouse model reduced the abundance of nutrient transporters on the cell surface. This was associated with increased urinary loss of lipids, amino acids, sugars, and proteins.

Further, the number of viral entry receptors on the cell surface dropped. The study found that treatment with a lipid kinase inhibitor decreased the entry of SARS-CoV-2 in cultured proximal tubular cells and human kidney organoids.

“In addition to inhibiting pinocytosis and autophagy, VPS34 depletion induced membrane exocytosis and reduced the abundance of the retromer complex necessary for proper membrane recycling and lipid retention, leading to a loss of fuel and biomass,” the study authors wrote.

The findings illustrate that blocking the enzyme lipid kinase may help to treat diseases in which reducing nutrient retention conveys a clinical benefit, such as kidney cancer or diabetes, or to block a kidney viral infection, according to the study authors.

“VPS34 inhibition abrogated SARS-CoV-2 infection in human kidney organoids and cultured proximal tubule cells in a glutamine-dependent manner,” the study authors concluded. “Thus, our results demonstrate that VPS34 adjusts endocytosis, nutrient transport, autophagy, and antiviral responses in proximal tubule cells in the kidney.”

Reference

Rinschen, M. et al. VVPS34-dependent control of apical membrane function of proximal tubule cells and nutrient recovery by the kidney. November 29, 2022. Science Signaling. https://www.science.org/doi/10.1126/scisignal.abo7940. Accessed December 5, 2022.

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