Publication Date:
2016-12-02
Description:
Homozygous inheritance of the hemoglobin S mutation (Hb SS; sickle cell anemia) affects 1 in 500 African Americans and is consistently associated with an increased risk for kidney disease, although the mechanisms are poorly understood. Heterozygous inheritance (Hb AS; sickle cell trait) affects 1 in 8 African Americans and has also been associated with an increased risk for kidney disease in some, but not all cohorts. We first investigated whether inheritance of the Hb S mutation resulted in incremental kidney damage in Hb AS and Hb SS mice compared to Hb AA mice using transgenic sickle mice 〉6 months old (Townes model, Jackson Laboratory). Using Masson trichrome stained sections of the kidney, patterns of mesangial expansion were determined in age- and sex-matched mice by a renal pathologist blinded to the hemoglobin genotype of each specimen. Hb AS mice had diffuse (〉50% of the glomeruli per slide being involved) mesangial expansion while Hb SS mice had diffuse and global (〉50% of the individual glomerulus being involved) mesangial expansion. Glomerular perimeters were measured using NanoZoomer Whole Slide Imaging in 26 randomly selected glomeruli from 2 mice per genotype. Using 〉300µm in circumference as the definition for an enlarged glomerulus, the proportion of enlarged glomeruli progressively increased from Hb AA to Hb AS to Hb SS mice (Cochran's test of linear trend, P=0.002)(Figure 1A). Progressively higher urine protein-to-creatinine ratios were also observed from Hb AA to Hb AS to Hb SS mice (Figure 1B; test for linear trend, P=0.03) as were progressively higher kidney weights: Hb AA (429±28mg, n=8), Hb AS (446±27mg, n=18), Hb SS (567±19mg, n=5) (Test for linear trend, P=0.047). We then compared the mRNA expression profiles in the kidney cortices, which predominantly include glomerular and proximal tubular cells, of 15 age- and sex-matched mice (5 per Hb genotype) using the Affymetrix Mouse Gene 2.0ST Array. Using an additive model with an FDR
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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