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

Abstract

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 γ (PPARγ) coactivator-1α (PGC-1α). 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.

Sirt3 deficiency promotes endothelial dysfunction and aggravates renal injury

“…Several studies have highlighted the role of Sirt3 in protecting from oxidative damage by its deacetylating activity of mitochondrial enzymes resulting in the regulation of ROS production and clearance [ 27 ]. Dikalova and colleagues showed that SIRT3 dictates vascular dysfunction by regulating oxidative stress via SOD2 [ 41 ], a direct target of SIRT3 deacetylase activity in the adult kidney [ 42 , 43 ]. In our setting, increased acetylation levels of SOD2 were found in Sirt3 -deficient mice, thus implying decreased anti-oxidant capacity of the kidney and further increased oxidative stress.…”

Sirtuins in kidney diseases: potential mechanism and therapeutic targets

“…NR supplementation proved beneficial in AKI with ischaemia‒reperfusion injury, as evidenced by a slowing increase of serum urea nitrogen and creatinine levels and tubular damage [ 186 ]. Restoration of Sirt3 activity, restoration of reduced glomerular numbers, improvement of glomerular podocyte density, and sparse density of renal capillaries by administration of NR supplementation to mothers on a low-protein diet provides a therapeutic option to potentially limit the long-term sequelae of a reduced kidney number in adulthood [ 183 ]. Intracellular NAMPT is a critical enzyme in the NAD + remediation synthesis pathway.…”

Nicotinamide Riboside, a Promising Vitamin B3 Derivative for Healthy Aging and Longevity: Current Research and Perspectives

“…NAD + supplementation, by oral administration of NAM, NA, NR, dihydronicotinamide riboside (reduced NR, NRH) and NMN, and SIRT activation may be useful in the prophylaxis and treatment of AKI, if some recent studies on MT metabolism are developed [ 109 , 110 , 111 , 112 , 113 ]. For example, in an experimental model of newborn (one day) mice from mothers fed a low protein diet, NRS restored the SIRT3 expression, by the induction of PGC-1α, improved MT and cellular protection against OXS, increasing the density of nephrons, renal capillaries, and glomerular podocytes [ 114 ].…”