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Abstract Polycystic kidney disease (PKD) is a genetic disorder characterized by bilateral cyst formation. We showed that PKD cells and kidneys display metabolic alterations, including the Warburg effect and glutaminolysis, sustained in vitro by the enzyme asparagine synthetase (ASNS). Here, we used antisense oligonucleotides (ASO) against Asns in orthologous and slowly progressive PKD murine models and show that treatment leads to a drastic reduction of total kidney volume (measured by MRI) and a prominent rescue of renal function in the mouse. Mechanistically, the upregulation of an ATF4–ASNS axis in PKD is driven by the amino acid response (AAR) branch of the integrated stress response (ISR). Metabolic profiling of PKD or control kidneys treated with Asns-ASO or Scr-ASO revealed major changes in the mutants, several of which are rescued by Asns silencing in vivo. Indeed, ASNS drives glutamine-dependent de novo pyrimidine synthesis and proliferation in cystic epithelia. Notably, while several metabolic pathways were completely corrected by Asns-ASO, glycolysis was only partially restored. Accordingly, combining the glycolytic inhibitor 2DG with Asns-ASO further improved efficacy. Our studies identify a new therapeutic target and novel metabolic vulnerabilities in PKD.

As recent trends in manufacturing engineering disciplines show a clear development in the sustainable as well as economically efficient design of forming processes, monitoring techniques have been gaining in relevance. In terms of monitoring of product properties, most processes are currently open-loop controlled, entailing that the microstructure evolution, which determines the final product properties, is not considered. However, a closed-loop control that can adjust and manipulate the process actuators according to the required product properties of the component will lead to a considerable increase in efficiency of the processes regarding resources and will decrease postproduction of the component. For most forming processes, one set of component dimensions will result in a certain set of product properties. However, to successfully establish closed-loop property controls for the processes, a systematic understanding of the reciprocity of the dimensions after forming and final product properties must be established. This work investigates the evolution of dimensional accuracy as well as product properties for a series of forming processes that utilize different degrees of freedom for process control.