Abstract
The metabolism of dietary proteins generates waste products that are excreted by the kidney, in particular nitrogen-containing urea, uric acid, ammonia, creatinine, and other metabolites such as phosphates, sulfates, and protons. Kidney adaptation includes an increase in renal plasma flow (RPF) and glomerular filtration rate (GFR) and represents a burden for diseased kidneys increasing the progression rate of CKD. The present study aimed at identifying potential differences between amino acid (AA) groups constituting dietary proteins regarding their impact on RPF, GFR, and CKD progression. We utilized the well-established 5/6 nephrectomy (5/6 Nx) CKD model in rats and submitted the animals for 5 weeks to either the control diet (18% casein protein) or to diets containing 8% casein supplemented with 10% of a mix of free amino acids, representing all or only a subset of the amino acids contained in casein. Whereas the RPF and GFR measured in free moving animals remained stable during the course of the diet in rats receiving the control mix, these parameters decreased in animals receiving the branched chain amino acid (BCAA) supplementation and increased in the ones receiving the aromatic amino acids (AAAs). In animals receiving essential amino acids (EAAs) containing both BCAAs and AAAs, there was only a small increase in RPF. The kidneys of the 5/6 Nx rats receiving the BCAA diet showed the strongest increase in smooth muscle actin and collagen mRNA expression as a result of higher level of inflammation and fibrosis. These animals receiving BCAAs also showed an increase in plasma free fatty acids pointing to a problem at the level of energy metabolism. In contrast, the animals under AAA diet showed an activation of AMPK and STAT3. Taken together, our results demonstrate that subsets of EAAs contained in dietary proteins, specifically BCAAs and AAAs, exert contrasting effects on kidney functional parameters and CKD progression.
Highlights
A high dietary protein load increases both renal plasma flow (RPF) and glomerular filtration rate (GFR) acutely and in the long term, and increases renal expression of proinflammatory genes (Hostetter et al, 1986; Tovar-Palacio et al, 2011; Juraschek et al, 2013)
After 6 weeks on normal control diet (CD) containing 18% casein (Figure 1A), we submitted these animals to different isocaloric diets containing 8% protein, supplemented with 10% of an amino acid mix containing one of the following: all amino acids as in casein (8 + 10), branched chain amino acids (BCAAs), aromatic amino acids (AAAs), essential amino acids (EAAs), or non-essential amino acids (NEAAs)
Parallel to the situation with AMPK, we noted in our experiments that phospho/total STAT3 was reduced in kidneys of chronic kidney disease (CKD) animals under BCAA diet, whereas it was increased in the kidney of rats under AAA diet compared to the 8 + 10 group (Figures 4A,B)
Summary
A high dietary protein load increases both renal plasma flow (RPF) and glomerular filtration rate (GFR) acutely and in the long term, and increases renal expression of proinflammatory genes (Hostetter et al, 1986; Tovar-Palacio et al, 2011; Juraschek et al, 2013). It appears crucial that renal adaptation to protein intake, including hyperfiltration, is necessary for the excretion of the nitrogenous end products (urea, ammonia, etc.) and other protein-associated wastes including acid equivalents due to the metabolism of sulfur-containing and cationic amino acids. This adaptation involves the combined effects of the hormones vasopressin and glucagon that together contribute to efficient urea excretion and water economy (Bankir et al, 2015, 2018). Submitting 5/6 Nx rats to these diets, we could demonstrate that the amino acid composition of the proteinaceous part of the diet differentially affects CKD progression
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