While studying how kidney filtration (endocytosis) is regulated for efficient nutrient capture by a lipid kinase (VPS34) in mice, an international team of scientists discovered that inhibiting the lipase kinase could prevent a viral infection. The team published its research “VPS34-dependent control of apical membrane function of proximal tubule cells and nutrient recovery by the kidney” in Science Signaling.

VPS 34 is involved in vesicular trafficking and endocytic sorting of membrane proteins. The team carried out a multiomics approach to the study which showed that a lack of lipid kinase in proximal kidney tubule cells in mice lowered the abundance of nutrient transporters on the cell surface, which was associated with increased urinary loss of lipids, amino acids, sugars, and proteins. In addition, the number of viral entry receptors on the cell surface was reduced. Subsequently, treatment with a lipid kinase inhibitor reduced the entry of the virus SARS-CoV-2 in cultured proximal tubular cells and human kidney organoids.

Gatekeeper for viral infections

“…by combining metabolomics, proteomics, and phosphoproteomics analyses with functional and superresolution imaging assays of mice with an inducible deficiency in proximal tubular cells, we revealed that VPS34 controlled the metabolome of the proximal tubule. 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,” write the investigators.

Schematic summary. [Science Signaling: DOI: 10.1126/scisignal.abo7940]

“Integration of omics data into a kidney cell metabolomic model demonstrated that VPS34 deficiency increased β-oxidation, reduced gluconeogenesis, and enhanced the use of glutamine for energy consumption. Furthermore, the omics datasets revealed that VPS34 depletion triggered an antiviral response that included a decrease in the abundance of apically localized virus receptors such as ACE2. VPS34 inhibition abrogated SARS-CoV-2 infection in human kidney organoids and cultured proximal tubule cells in a glutamine-dependent manner. “Thus, our results demonstrate that VPS34 adjusts endocytosis, nutrient transport, autophagy, and antiviral responses in proximal tubule cells in the kidney.

The study showed that blocking the lipid kinase could be used to treat diseases in which limiting the retention of nutrients gives clinical benefit, such as kidney cancer or diabetes, or to block a viral infection of the kidney.

“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,” said Markus Rinschen, MD, first-author of the study and Associate Professor at the Aarhus Institute of Advanced Studies and the Department of Biomedicine at Aarhus University. “Of course, more knowledge needs to be gathered before any conclusions regarding human relevance can be made.”

The study involved a collaboration among researchers at Aarhus University, the University Hospital Hamburg Eppendorf, University of Kiel, and University of Michigan.