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Renal hypertrophic signaling triggers activation of kidney immune response and accelerates cystogenesis in polycystic kidney disease
Author(s) -
Saigusa Takamitsu,
Huang Jifeng,
He Lan,
Yoder Bradley K,
Zimmerman Kurt A,
Bell P. Darwin
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.747.1
Subject(s) - pkd1 , polycystic kidney disease , kidney , autosomal dominant polycystic kidney disease , endocrinology , medicine , kidney disease , renal function , muscle hypertrophy , biology
Background Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease with the predominant form resulting from mutations in the gene, PKD1. The disease severity is highly variable even among families with the same PKD1 gene mutation and factors other than genetics may affect cystogenesis. Protein load or unilateral nephrectomy (UNx: 1K) results in glomerular hyperfiltration and renal hypertrophy which both accelerates kidney cyst growth in PKD mice. Children with PKD that exhibit glomerular hyperfiltration were shown to have a higher rate of cyst growth and faster decline in kidney function. Thus, hypertrophic signaling in PKD may clinically be a risk factor to accelerate cystogenesis. Methods To test the effect of renal hypertrophy in PKD, we used adult tamoxifen inducible Pkd1 flox/flox mice with or without CAGG‐cre. Three weeks after cre induction, first group of mice underwent sham surgery or UNx to accelerate cyst formation and observed for 3 or 6 weeks. The second group of mice were fed with either high protein (60%), normal protein (18%) or low protein diet (6%) for a total of 6 weeks. Mice from both UNx and modified protein diet group were sacrificed at the end of the experiment and kidneys were harvested for RNA‐seq, histology, inflammatory cytokines and flow cytometry for kidney immune cell sorting. Results Analysis of RNA sequencing data revealed that 1K compared to intact two kidney (2K) Pkd1 deficient mice show differentially expressed genes involved in activating/recruiting macrophages and production of pro‐inflammatory cytokines during the hypertrophic signaling. 1K compared to 2K Pkd1 mice had increased number of resident macrophage (CD11b lo , F4/80 hi ) but not infiltrating macrophages (CD11b hi , F4/80 lo ), increased inflammatory cytokine production, and severe cystic kidneys. Pkd1 deficient mice that were given a high protein diet compared to a low protein diet, resulted in activation of kidney immune cells, recruitment of inflammatory cytokines and worsening kidney cysts. Conclusions Renal hypertrophic signaling triggered by either UNx or protein load in adult Pkd1 mice activates kidney immune cells, inflammatory cytokine production and accelerates cyst growth. Support or Funding Information NIH K08DK106465, P30 DK074038, T32AI007051 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .