Sickle cell nephropathy (SCN) is a leading cause of morbidity and mortality in
sickle cell disease (SCD). Early intervention is crucial for mitigating its effects. However, current diagnostic methods rely on generic tests and may not detect SCN until irreversible renal damage occurs. Therefore, specific
biomarkers for early diagnosis of SCN are needed. Urinary exosomes, membrane-bound vesicles secreted by renal podocytes and epithelial cells, contain both common and cell type-specific membrane and cytosolic
proteins, reflecting the physiologic and pathophysiologic states of the kidney. Using proteomics, we analyzed the
proteomes of urinary exosomes from humanized SCD mice at 2 months (without
albuminuria) and 4 months (with
albuminuria) of age. Excretion of 164
proteins were significantly increased and 176
proteins was significantly decreased in the exosomes when mice developed
albuminuria. Based on the relevance to SCD,
chronic kidney disease and Western blot confirmation in mice, we analyzed
protein abundance of
heparanase,
cathepsin C, α2-macroglobulin and sarcoplasmic endoplasmic Ca2+ ATPase-3 (SERCA3) in the urinary exosomes and urine of 18 SCD subjects without
albuminuria and 12 subjects with
albuminuria using Western blot analyses. Both male and female subjects increased or tended to increase the excretion of these
proteins in their urinary exosomes upon developing
albuminuria, but female subjects demonstrated stronger correlations between the excretion of these
proteins and urine
albumin creatinine ratio (UACR) compared to male subjects. In contrast, exosomal excretion of
Tamm-Horsfall protein, β-actin and SHP-1 was independent of
albuminuria. These findings provide a foundation for a time-course study to determine whether increases in the levels of these
proteins precede the onset of
albuminuria in patients, which will help determine the potential of these
proteins as
biomarkers for early detection of SCN.