Wheat-Based Protein Slows Disease Progression in <i>Pkd1</i> Knockout Mice

Dietary load and composition are known contributors that accelerate cyst growth in polycystic kidney disease (PKD). High protein intake, which increases amino acid burden in the kidneys, is one such factor. Despite identical protein load, a plant-based wheat-gluten (WG) diet was recently reported to blunt the inflammatory response of animal-based casein diet in a hypertensive model. Considering the importance of pro-inflammatory signals on cystogenesis in PKD, we therefore sought to determine whether a WG compared to casein diet would decelerate cyst progression. Tamoxifen-inducible, global Pkd1 knockout mice were fed either a low casein (6%), high casein (60%), or high wheat-gluten (60%) protein diet for 6 wk. In a separate cohort, mice were gavaged daily with vehicle, lysine, or glutamine for 4 wk while maintained on a normal protein (18%) diet. Tissues were used for histology, flow cytometry, mitochondrial function, metabolomics, and various biochemical assays. WG-fed mice had better kidney function and reduced kidney macrophage percentages, proinflammatory cytokine expression, and cyst growth compared to casein-fed mice. Protein source did not alter kidney mitochondria function. Supplementation with lysine, the highest amino acid in casein versus WG diet, increased kidney cyst growth, acid production, and metabolic disarray. This did not occur with glutamine supplementation, the highest amino acid in WG versus casein diet, despite increased glomerular filtration rate with both amino acids. Neither supplementation mounted an inflammatory response. A plant-based, low-lysine diet slows disease burden in a murine model of PKD. This easily modifiable diet may be a beneficial intervention for PKD patients.