Our Lab Focus: Dietary protein load, immune response and kidney cyst progression
See a complete list of published works here.
Current Research Projects in the Saigusa Lab
Unilateral nephrectomy increases macrophage-driven inflammation and accelerates kidney cyst growth in polycystic kidney disease (PKD) mice
Adult conditional, global Pkd1 knockout (Pkd1KO) mice exhibit slow kidney cyst growth, however environmental factors can hasten kidney cyst expansion. Bell PD et. al. first demonstrated that inducing injury via unilateral nephrectomy (removing one kidney) accelerates cystogenesis in conditional Ift88KO mice https://doi.org/10.1681%2FASN.2010050526. We similarly observed this phenomenon in Pkd1KO mice. Fitzgibbon WR et al. https://doi.org/10.1152/ajprenal.00389.2017.
Accelerated kidney cyst growth is associated with increased numbers of tissue resident macrophages (MФ), pro-inflammatory cytokines, and inflammation in early stages of PKD. Interferon regulatory factor 5 (IRF5), a MФ transcription factor that induces a pro-inflammatory state, was increased in nephrectomized Pkd1KO mice compared to non-nephrectomized counterparts. Antisense oligonucleotides that inhibit Irf5 expression reduced kidney tissue resident MФ Irf5 and Il6 expression, Stat3 abundance, and cyst growth. This indicates that tissue resident MФs and pro-inflammatory cytokines accelerate cystogenesis in response to unilateral nephrectomy. Zimmerman KA et al. https://doi.org/10.34067/KID.0001052019.
High dietary protein intake increases inflammation and cystogenesis in PKD
A high protein diet is another well-known environmental factor that can increase renal blood flow and stimulate kidney and cyst growth in PKD. Similar to the unilateral nephrectomy model, high protein (casein) intake increases MФ -driven inflammation and cyst expansion. In very early stages of dietary protein load, kidney cyst growth precedes the increase in MФ numbers or pro-inflammatory cytokines. High protein diet elevated the expression of glutamine transporter Snat3 and gluconeogenesis marker Pepck1 alongside increases in urinary ammonia in Pkd1KO mice. This indicates that glutamine, the most abundant amino acid in high protein diet, is an early stimulator of cyst growth in PKD. Sedaka R et al. https://doi.org/10.3389/fmed.2023.1173674.
When Pkd1KO mice are fed a plant-based (wheat-gluten) high protein diet in lieu of the typical animal-based (casein) high protein diet, it mitigates the kidney immune response and slows the rate of cyst growth. Sedaka R et al. https://doi.org/10.1093/function/zqaf026 . Supplementation of lysine, the most abundant amino acid in animal based protein compared to wheat leads to metabolic stress, acid accumulation and accelerates cyst progression. However, glutamine, which is abundant in wheat protein, did not stimulate cyst growth despite both lysine and glutamine increased GFR. Protein source did not affect mitochondrial function but metabolomics profile revealed clear sex differences related to impaired mitochondrial electron transport, which may explain why female were more resistant to diet intervention. While the benefits of wheat protein remain unknown in PKD patients, consuming wheat protein is safe and modifying dietary protein source to one containing less lysine could be an appreciable long-term intervention.
Intestinal epithelial integrity declines during late-stage PKD
Despite its role as the body’s largest inflammatory cell reservoir, the potential contribution of the intestines to PKD development has yet to be elucidated. Utilizing Pkd1KO mice, we uncovered that the intestinal barrier is less permeable in early PKD while cyst growth initiates but becomes leakier as kidney disease progresses and cysts are enlarged. Sedaka R et al. https://doi.org/10.1152/ajprenal.00058.2024. Our current research is focused on the physiological implications of these findings and expanding upon the PKD intestinal phenotype.
