An RNA transmethylation pathway governs kidney nephrogenic potential

Area of Science:

• Nephrology
• Developmental Biology
• Molecular Metabolism

Background:

• Adult kidneys cannot generate new nephrons, increasing risks for chronic kidney disease (CKD) in individuals with fewer nephrons.
• Nephron formation is hindered by limited nutrient availability, but key metabolic dependencies are not fully understood.

Purpose of the Study:

• To investigate the role of S-adenosylmethionine (SAM) and cellular transmethylation in kidney nephrogenesis.
• To identify molecular mechanisms regulating nephron progenitor cell (NPC) differentiation and nephron production.

Main Methods:

• Assessed the impact of modulating transmethylation status and METTL3 activity on NPC differentiation and nephrogenesis.
• Utilized RNA immunoprecipitation followed by sequencing to identify direct targets of METTL3.
• Investigated the role of Lrpprc mRNA in mediating the effects of SAM and METTL3 on nephrogenesis.

Main Results:

• Cellular transmethylation status and SAM levels are critical for nephrogenic capacity.
• The RNA methyltransferase METTL3 acts as a SAM sensor, essential for NPC fate determination.
• Inhibition of METTL3 or transmethylation blocks NPC differentiation, while enhancement promotes nephron production.
• Lrpprc mRNA, encoding a mitochondrial protein, is a direct target of METTL3-mediated methylation.
• Inhibition of LRPPRC counteracts the nephrogenic effects of SAM and METTL3.

Conclusions:

• A methionine-SAM-RNA transmethylation pathway regulates nephron formation.
• METTL3 and its target Lrpprc are key components of this pathway.
• Targeting this pathway offers a potential strategy to enhance nephrogenesis and combat kidney disease.