Dietary supplementation with essential amino acids boosts the beneficial effects of rosuvastatin on mouse kidney

Abstract

The effects of high-potency statins on renal function are controversial. To address the impact of statins on renal morpho-functional aspects, normotensive young mice were treated with rosuvastatin (Rvs). Moreover, because statins may impair mitochondrial function, mice received either dietary supplementation with an amino acid mixture enriched in essential amino acids (EAAm), which we previously demonstrated to increase mitochondrial biogenesis in muscle or an unsupplemented control diet for 1 month. Mitochondrial biogenesis and function, apoptosis, and insulin signaling pathway events were studied, primarily in cortical proximal tubules. By electron microscopy analysis, mitochondria were more abundant and more heterogeneous in size, with dense granules in the inner matrix, in Rvs- and Rvs plus EAAm-treated animals. Rvs administration increased protein kinase B and endothelial nitric oxide synthase phosphorylation, but the mammalian target of rapamycin signaling pathway was not affected. Rvs increased the expression of sirtuin 1, peroxisome proliferator-activated receptor γ coactivator-1α, cytochrome oxidase type IV, cytochrome c, and mitochondrial biogenesis markers. Levels of glucose-regulated protein 75 (Grp75), B-cell lymphoma 2, and cyclin-dependent kinase inhibitor 1 were increased in cortical proximal tubules, and expression of the endoplasmic reticulum–mitochondrial chaperone Grp78 was decreased. EAAm supplementation maintained or enhanced these changes. Rvs promotes mitochondrial biogenesis, with a probable anti-apoptotic effect. EAAm boosts these processes and may contribute to the efficient control of cellular energetics and survival in the mouse kidney. This suggests that appropriate nutritional interventions may enhance the beneficial actions of Rvs, and could potentially prevent chronic renal side effects.

Dietary Modifications of Nitrogen Intake Decreases Inflammation and Promotes Rejuvenation of Spleen in Aged Mice

“…The main message from our data is that the EAA-rich diet could improve spleen health of aged animals by reducing inflammation and by increasing chaperones and cell survival markers. Similar results have already been reported in muscles, liver, heart and kidneys [19,21,23,25] but to our knowledge, it is the first time that these results have been reported in the far less considered spleen.…”

“…We have shown that aged mice with a diet supplemented with a balanced EAA formulation increases lifespan, improves mitochondrial biogenesis and morphological and molecular changes in the heart, skeletal muscle and adipose tissues [19,20,21,22]. The protective role of an EAA rich diet was also observed in rat livers with chronic ethanol consumption [23,24], in the kidneys of rosuvastatin-treated mice [25] and during wound healing [26]. Furthermore, in vitro data showed that variations in the EAA/NEAA concentration ratio regulates cancer cell survival or death [27].…”

Body Weight Loss, Tissue Wasting and Shortened Lifespan in Late Middle-aged Mice on Imbalanced Essential/Non-essential Amino Acids Diet

“…This may indicate that excess EAAs possesses anti-inflammatory properties. This is in line with our previous studies showing that dietary supplementation with balanced EAAs mixtures reduced oxidative stress, thus slowing cellular aging [3,5,7,9]. This is also confirmed by our newlycompleted lifespan experiment showing that weaned male mice fed with EAA-rich diets live longer (about over 10%) than those fed StD (25 vs 22 months respectively).…”

“…1) The EAA-exclusive diet (EAA-Ex) contained EAAs (100%) as the unique source of N, in a formulation tailored to mammal needs [14] and widely applied in clinical and experimental studies [3,5,7,9,10,15].…”

Nutrition, Nitrogen Requirements, Exercise and Chemotherapy-Induced Toxicity in Cancer Patients. A puzzle of Contrasting Truths?

“…Moreover, the ROS defense genes were upregulated, and ROS production was reduced [99]. EAA supplementation was also effective in reducing damage caused by alcohol in the liver and by rosuvastatin in the kidney [146,147]. Together, these studies offer a rationale for exploring the role of EAA in preventing and controlling chemotherapy-induced toxicity.…”