Reduced Renal Primary Cilia Expression in Humanized Sickle Cell Mice

Sickle cell disease (SCD) is an autosomal recessive hematologic disorder that afflicts millions of people across the globe. As longevity improves due to therapeutic advancements, end‐organ damage, namely sickle cell nephropathy (SCN), has emerged as a major contributor to mortality and morbidity in these patients. Renal primary cilia are mechanosensory organelles that extend from the apical membrane of epithelial cells throughout the nephron and contribute to structural homeostasis. Studies have shown that renal primary cilia display alterations in response to renal ischemic injury and are essential in the epithelial repair process. Defects in renal primary cilia expression and signaling have been shown to contribute to the development of renal cystogenesis. In addition, recent studies have demonstrated an increased prevalence of renal cyst formation in sickle cell disease patients. Therefore, we hypothesized that renal primary cilia expression is reduced in a mouse model of sickle cell disease. We further predicted that acute hypoxia challenge will reduce renal primary ciliogenesis in SCD animals compared to controls. Male 14‐week old humanized sickle cell mice (HbSS) and their genetic controls (HbAA) were subjected to 3 hr exposure to hypoxia (10% O 2 ) prior to the assessment of renal primary cilia formation. Cilia formation was assessed using Western blot analysis on kidney section lysates. Prior to hypoxia exposure, acetylated □‐tubulin expression, a protein involved in cilia architecture, was reduced in the cortex of HbSS mice compared to the genetic controls (0.45 ± 0.02 vs. 1 ± 0.02 a.u. [arbitrary units], respectively, p= 0.03, n=4). In addition, IFT88 expression, a protein involved in cilia assembly, was also reduced in the cortex of HbSS mice compared to HbAA mice (0.59 ± 0.00 vs. 1 ± 0.001, respectively, p= 0.02, n=4). After a 3 hr hypoxia challenge, HbSS mice maintained a significant reduction in cortical acetylated □‐tubulin expression compared to hypoxia‐ challenged HbAA mice (0.38 ± 0.02 vs. 1 ± 0.03 a.u., respectively, p= 0.008, n=5). However, there was no significant difference in cortical IFT88 expression in HbSS mice compared to controls following hypoxia (1.1± 0.002 vs. 1 ± 0.002 a.u., respectively, p= 0.69, n=5). These data suggest that renal primary cilia expression is reduced in SCD and acute hypoxia exposure may promote renal ciliogenesis. These findings provide a potential mechanism by which renal injury is potentiated in SCN. Support or Funding Information William Townsend Porter Pre‐ doctoral Fellowship from the American Physiological Society to C. Taylor U01 HL117684 to DMP This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .