Low Nephron Number Induced by Maternal Protein Restriction Is Prevented by Nicotinamide Riboside Supplementation Depending on Sirtuin 3 Activation

A reduced nephron number at birth, due to critical gestational conditions, including maternal malnutrition, is associated with the risk of developing hypertension and chronic kidney disease in adulthood. No interventions are currently available to augment nephron number. We have recently shown that sirtuin 3 (SIRT3) has an important role in dictating proper nephron endowment. The present study explored whether SIRT3 stimulation, by means of supplementation with nicotinamide riboside (NR), a precursor of the SIRT3 co-substrate nicotinamide adenine dinucleotide (NAD(+)), was able to improve nephron number in a murine model of a low protein (LP) diet. Our findings show that reduced nephron number in newborn mice (day 1) born to mothers fed a LP diet was associated with impaired renal SIRT3 expression, which was restored through supplementation with NR. Glomerular podocyte density, as well as the rarefaction of renal capillaries, also improved through NR administration. In mechanistic terms, the restoration of SIRT3 expression through NR was mediated by the induction of proliferator-activated receptor gamma (PPAR gamma) coactivator-1 alpha (PGC-1 alpha). Moreover, NR restored SIRT3 activity, as shown by the reduction of the acetylation of optic atrophy 1 (OPA1) and superoxide dismutase 2 (SOD2), which resulted in improved mitochondrial morphology and protection against oxidative damage in mice born to mothers fed the LP diet. Our results provide evidence that it is feasible to prevent nephron mass shortage at birth through SIRT3 boosting during nephrogenesis, thus providing a therapeutic option to possibly limit the long-term sequelae of reduced nephron number in adulthood.

Automated summary

Reduced nephron number at birth, associated with critical gestational conditions, may increase the risk of hypertension and chronic kidney disease in adulthood. This study investigated the potential of stimulating SIRT3 expression through nicotinamide riboside (NR) supplementation to improve nephron number in a murine model on a low protein (LP) diet. The findings showed that NR supplementation restored SIRT3 expression, improved glomerular podocyte density and preserved renal capillaries, possibly through activation of PGC-1 alpha. Furthermore, NR restored SIRT3 activity, resulting in improved mitochondrial morphology and protection against oxidative damage. These results suggest that boosting SIRT3 during nephrogenesis may prevent nephron mass shortage at birth.