Monday, December 30, 2024
12/30/2024
Autosomal dominant polycystic kidney disease (ADPKD), is caused by mutations in PKD1 or PKD2 genes. Disease severity is highly variable, even among families with the same PKD gene mutation. This variability has been attributed, in part, to environmental factors. Among them, a high protein diet is one of the most recognized ADPKD progression-accelerating factor. Protein composition is also a key element that can affect the rate of cyst growth. For example, soy protein compared to casein (animal-based protein) diet slows kidney cyst in rodent PKD models. Our preclinical data shows that wheat gluten (WG) diet compared to casein protein diet decreased the number of kidney macrophages (MФ), expression of Ccl2 (but not Csf1 or Ccl5) and slowed the rate of cyst growth in Pkd1-knockout mice. Therefore, animal-based protein load may have cystogenesis-promoting effects through augmentation of the cystogenesis-promoting Ccl2 pathway. Previous studies show that loss of Pkd1 increases Ccl2 in the renal tubules facilitating the recruitment of MФ, promoting kidney cyst growth and that these effects were attenuated in Ccl2-Pkd1 double knockout mice. We found that animal protein load impairs kidney mitochondrial function in Pkd1-knockout mice. When these mice were fed a WG diet enriched with top 3 amino acids abundant in casein compared to WG diet, there was increased number of kidney MФ and cyst growth compared to counterparts fed an isocaloric WG diet. This suggest that specific AAs in the casein diet promotes cyst growth. Furthermore, treatment with lysine (most abundant AA in casein compared to WG diet), but not aspartate (second abundant in casein) or glutamate (most abundant in WG), suppressed markers of mitochondrial function, impaired glucose metabolism, increased gluconeogenesis marker phosphoenolpyruvate (Pepck1) and increased tubular injury in Pkd1 mouse kidney cells. Oral lysine supplementation (1wk) in Pkd1 knockout mouse increased kidney cyst growth and levels of Pepck1 compared to counterparts given a saline. These data are well aligned with a major role kidneys play in AA metabolism through the mitochondria, an organelle that is functionally impaired by PKD mutations. Our overarching hypothesis is that specific AA(s) abundant in an animal protein-based diet exacerbate mitochondrial dysfunction, increase chemokine expression, MФ recruitment, and accelerate cystogenesis. Aim1 will test the hypothesis that high casein-protein diet impairs mitochondrial function, activates chemokine Ccl2 expression, increases kidney MФ accumulation, and promotes cyst growth; and deletion of Ccl2 in Pkd1-knockout mice have opposite effects. Aim2 will test the hypothesis that specific AA (lysine) abundant in an animal-based protein diet compared to a plant-based diet, leads to mitochondrial dysfunction, increased immune response and accelerated cyst growth. The clinical significance of this grant proposal is that patients with PKD could benefit from a plant-based protein diet and recent plant-based meat development has made dietary protein modification a feasible intervention that is safe and can have immediate impact for patients with ADPKD that require long-term treatment.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).