Increased Circulating and Urinary Levels of Soluble TAM Receptors in Diabetic Nephropathy

Abstract

TAM receptors (Tyro3, Axl, and Mer) have been implicated in innate immunity. Circulating TAM receptor soluble forms (sTyro3, sAxl, sMer) are related to autoimmune disorders. We investigated TAM and their ligand protein S in patients with diabetes. Urinary and plasma levels of protein S, sTyro3, sAxl, and sMer were determined in 126 patients with diabetes assigned to a normoalbuminuric or macroalbuminuric (urinary albumin excretion <30 mg/24 hours and >300 mg/24 hours, respectively) study group and 18 healthy volunteers. TAM and protein S immunostaining was performed on kidney biopsy specimens from patients with diabetic nephropathy (n = 9) and controls (n = 6). TAM expression and shedding by tubular epithelial cells were investigated by PCR and enzyme-linked immunosorbent assay in an in vitro diabetes model. Patients with macroalbuminuria diabetes had higher circulating levels of sMer and more urinary sTyro3 and sMer than normoalbuminuric diabetics. Increased clearance of sTyro3 and sMer was associated with loss of tubular Tyro3 and Mer expression in diabetic nephropathy tissue and glomerular depositions of protein S. During in vitro diabetes, human kidney cells had down-regulation of Tyro3 and Mer mRNA and increased shedding of sTyro3 and sMer. Renal injury in diabetes is associated with elevated systemic and urine levels of sMer and sTyro3. This is the first study reporting excretion of sTAM receptors in urine, identifying the kidney as a source of sTAM.

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“…Indeed, sMer shedding has been reported to be associated with numerous diseases, such as systemic lupus erythematosus (40), multiple sclerosis (37), primary Sjogren's syndrome (18), and diabetic nephropathy (17). In the present study, we find that sMer can also be released into the peripheral circulation.…”

Study the Association of Tumor Necrosis Factor Promoter Polymorphism with Type 2 Diabetic Nephropathy

“…The results revealed that the duration of diabetes was longer in DN than DM. This agreed with Mahfouz et al [15]; meanwhile, Ochodnicky et al [16] and Motawi et al [17] reported that there was no significant difference in the duration of diabetes between DM and DN. The relation between DN and duration of diabetes was explained by Gallagher and Suckling [18] who reported that prolonged exposure to hyperglycemia causes damage to kidney structures, either directly or through hemodynamic changes.…”

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“…25,26 However, a more recent study shows that the plasma PS level did not change between normal controls, patients with diabetes with or without DN. 27 The discrepancy among these studies could be due to the use of different assays and/or the heterogeneity of patient populations. Further studies with more standardized protocols and larger numbers of patient populations are required to reconcile the discrepant findings.…”