Abstract
Diabetic nephropathy (DN) is among the most serious complications of diabetes mellitus, and often leads to end-stage renal disease ultimately requiring dialysis or renal transplantation. The loss of podocytes has been reported to have a role in the onset and progression of DN. Here, we addressed the activation mechanism of Smad3 signaling in podocytes. Expression of RII and activation of Smad3 were induced by AGE exposure (P<0.05). Reduction of the activation of RII-Smad3 signaling ameliorated podocyte injuries in Smad3-knockout diabetic mice. The bone morphogenetic protein 4 (BMP4) significantly regulated activation of RII-Smad3 signalings (P<0.05). Moreover, the epithelium-specific transcription factor, Elf3was induced by AGE stimulation and, subsequently, upregulated RII expression in cultured podocytes. Induction of Elf3 and activation of RII-Smad3 signaling, leading to a decrease in WT1 expression, were observed in podocytes in diabetic human kidneys. Moreover, AGE treatment induced the secretion of Elf3-containing exosomes from cultured podocytes, which was dependent on the activation of the TGF-β-Smad3 signaling pathway. In addition, exosomal Elf3 protein in urine could be measured only in urinary exosomes from patients with DN. The appearance of urinary exosomal Elf3 protein in patients with DN suggested the existence of irreversible injuries in podocytes. The rate of decline in the estimated Glomerular Filtration Rate (eGFR) after measurement of urinary exosomal Elf3 protein levels in patients with DN (R2 = 0.7259) might be useful as an early non-invasive marker for podocyte injuries in DN.
Highlights
Diabetic nephropathy (DN) is a morbid complication associated with diabetes mellitus and is the leading cause of end-stage renal disease (ESRD) [1]
Glomerular WT1 expression was significantly decreased in db/db mice compared with Smad3+/-;db/db mice, suggesting that activation of Smad3 signalings is involved in podocyte damage
We were able to detect a significant induction of RII and activation of Smad3, and decreased expression of WT1 protein in advanced glycation end-products (AGEs)-treated podocytes (Fig 1C and 1D)
Summary
Diabetic nephropathy (DN) is a morbid complication associated with diabetes mellitus and is the leading cause of end-stage renal disease (ESRD) [1]. Podocytes are highly specialized epithelial cells located on the surface of the glomeruli capillaries and normally prevent leakage of proteins into urine [2, 6]. Since these cells are unable to divide, their injury and malfunction leads to proteinuria, accumulation of extracellular matrix (ECM) components, and eventually results in irreversible glomerulosclerosis. Exosomes are 40–100 nm membrane vesicles secreted into the extracellular space by numerous cell types These structures can be isolated from body fluids including urine and plasma [12].
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