High protein diet increases kidney macrophages and accelerates polycystic kidney disease

Background Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease that leads to end stage renal disease. Interestingly, the disease severity is highly variable even among families with the same gene mutation, suggesting factors other than genetics may affect cystogenesis. One factor that accelerates cystogenesis in PKD rodent is a high protein diet that results in renal hypertrophy. However, the mechanism of how a high protein diet promotes cystogenesis is unknown. We have shown that renal hypertrophy triggered by unilateral nephrectomy increases kidney macrophages and accelerates cystogenesis in ADPKD mouse. Therefore, we hypothesize that a high protein diet fed in ADPKD mice leads to increased kidney macrophages and accelerates cyst growth similar to a unilateral nephrectomy model. Methods We used adult tamoxifen inducible Pkd1 flox/flox mice with or without Cagg cre‐ER. These adult conditional Pkd1 knockout mice typically requires months to develop major kidney cysts. Three weeks after cre induction, mice were fed with either a high protein (HP: 60%), a normal protein (NP: 18%) or a low protein (LP: 6%) diet for a total of 1 and 6 weeks. Some mice were given a HP diet and treated either with liposomal clodronate (to deplete macrophage) or with PBS (IP twice a week) for a total of 6 weeks. All mice were sacrificed at the end of the experiment and kidneys were harvested for histology, cytokines and flow cytometry for kidney immune cell sorting. Results Pkd1 mice fed a HP diet for 6 weeks resulted in increased number of kidney resident macrophage (CD11b lo , F4/80 hi ) and infiltrating macrophages (CD11b hi , F4/80 lo ) compared to kidneys from a NP or LP diet fed mice. A HP diet resulted in increased kidney pro‐inflammatory cytokines, chemokine and developed severe kidney cysts compared to a NP or LP diet group. Pkd1 mice treated with liposomal clodronate had fewer resident and infiltrating macrophages and smaller kidneys compared to control PBS treated group. Interestingly, mice fed a HP diet for 1 week already had larger kidneys compared to those fed a LP diet, but there were no differences in kidney chemokines or tubular injury marker. Conclusions Renal hypertrophy triggered by a HP diet increases kidney macrophages, inflammatory cytokine production and promotes cyst growth in adult Pkd1 mice. The mechanism of how dietary protein initiates and accelerates cyst growth remains to be determined. Support or Funding Information NIH/NIDDK K08 DK106465, R03 DK119717 PKD Foundation 232G19a