Dietary Lysine Supplementation Causes Metabolic Dysregulation and Kidney Cyst Growth in Mice with Polycystic Kidney Disease

Background: High casein protein diet induces renal hypertrophy, macrophage (MΦ) infiltration, and accelerated cyst growth in polycystic kidney disease (PKD) mice. Early cyst growth during casein protein load is associated with higher expression of glutamine transporter Snat3 and energy metabolism markers prior to increases in kidney MΦ number. It is unknown whether plant-based protein similarly exacerbates PKD. Here, we determined the effect of wheat- or casein-based diet on cyst growth, as well as how specific amino acids abundant in these respective diets contribute to disease progression in mice lacking Pkd1. Methods: Adult tamoxifen inducible global Pkd1 knockout (Pkd1KO) mice were fed a high protein (60%) casein or wheat-gluten (WG) diet for 6 weeks. Kidneys were harvested for histology, MΦ quantification, and mitochondrial function. The most abundant amino acid in casein and WG diets were Lysine (Lys) and glutamine (Gln), respectively. Thus, Pkd1KO mice were gavaged with Lys (6.8g/kg/day), Gln (5.3g/kg/day) or phosphate buffered saline (PBS) for 4 weeks to assess cyst growth, glomerular filtration rate (GFR) and kidney tissue analysis. Results: WG-fed Pkd1KO mice had fewer kidney MΦs, cytokines and cysts versus casein-fed counterparts. Mitochondrial oxygen consumption rate was similar between diets. Although both Lys and Gln gavaged Pkd1KO mice had higher GFR compared to PBS treated counterparts, only Lys gavaged mice had increased kidney cysts with higher expression of energy metabolism and fatty acid catabolism markers. Further, Lys treated mice had elevated renal Snat3 expression and urinary ammonia excretion, but lower blood urea nitrogen compared to Gln counterparts. Neither Lys nor Gln supplementation altered inflammatory cytokine expression relative to PBS treated mice. Conclusion: Plant-based protein retarded the inflammation and cyst growth observed in casein-fed Pkd1KO mice. Lys, the most abundant amino acid in casein versus WG diet, increased Gln transport, energy metabolism and cyst growth in early PKD. Funding: NIDDK Support