Longitudinal study of renal phenotype in mouse model of sickle cell trait

Abstract

Background: Sickle cell disease (SCD) is an autosomal recessive blood disorder caused by mutations in the β-globin gene, resulting in hemoglobin S (HbS) polymerization and red blood sickling. SCD patients carry two copies of the mutant HbS (HbSS) and develop anemia, iron overload and to end-organ damage. Heterozygous carriers (AS) are said to have sickle cell trait (SCT). While not associated with shortened life expectancy, individuals with SCT are at increased risk for a limited number of complications, including chronic kidney disease (CKD) that has yet to be fully elucidated. Our objective was to examine if mouse model of SCT is associated with worsening kidney function over time, mimicking an increased risk of CKD in SCT. Methods: We used male humanized sickle cell trait (HbAS) and age-matched genetic control (HbAA) mice (n=18). Analysis of urinary renal biomarkers (albuminuria, proteinuria, kidney injury marker 1 (KIM-1), osmolality) and time course of kidney function (determined via transcutaneous measurement of glomerular filtration rate (GFR)) were conducted in 4-week intervals from 12 to 40 weeks of age. Results: At 8 weeks of age, HbAS mice exhibited no differences in GFR, or proteinuria compared to HbAA controls. Significant increase in GFR, but not proteinuria, was observed in HbAS at 16 weeks of age compared to HbAA mice (241.6±5.3 ul/min vs 218.2±5 ul/min, respectively, p ˂0.05). Importantly, significant loss of kidney function measured by GFR (200 ± 3 vs 217.9 ± 3.2 ul/min, p<0.05) and twofold increase in proteinuria (4.6 ±1.1 vs 2.3 ±0.4 mg/24h, p<0.05) were observed at 36 weeks old HbAS mice when compared to age-matched controls. Following the increase in GFR at 16 weeks of age, HbAS developed mild degree of glomerular damage presented with subsequent slow increase in albuminuria over time (pgen<0.0001; page<0.0001, pinter=0.001). Interestingly, increased levels of urinary KIM-1 excretion, marker of tubular damage, were observed in HbAS mice throughout the duration of the study, with the highest levels at 16 weeks (228.3 ± 32.6 pg/24h vs 53.8 ± 8.5 pg/24h, respectively, p˂0.05). Urine osmolality was not different at 8 weeks of age, but progressively declined throughout the duration of the study in HbAS mice vs controls (1946 ±63 vs 2672 ±135 mOsm/kg at 36 weeks, p=0.002). Conclusion: Humanized sickle cell trait mice develop progressive loss of kidney function and associated renal injury over time. Funding: NHLBI–R00HL144817 and NHLBI-R01 HL157441 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.