Abstract
Background We previously observed that adenosine A1 receptor (A1AR) had a protective role in proximal tubular megalin loss associated with albuminuria in diabetic nephropathy (DN). In this study, we aimed to explore the role of A1AR in the fibrosis progression of DN. Methods We collected DN patients' samples and established a streptozotocin-induced diabetes model in wild-type (WT) and A1AR-deficient (A1AR−/−) mice. The location and expression of CD34, PDGFRβ, and A1AR were detected in kidney tissue samples from DN patients by immunofluorescent and immunohistochemical staining. We also analyzed the expression of TGFβ, collagen (I, III, and IV), α-SMA, and PDGFRβ using immunohistochemistry in WT and A1AR−/− mice. CD34 and podoplanin expression were analyzed by Western blotting and immunohistochemical staining in mice, respectively. Human renal proximal tubular epithelial cells (HK2) were cultured in medium containing high glucose and A1AR agonist as well as antagonist. Results In DN patients, the expression of PDGFRβ was higher with the loss of CD34. The location of PDGFRβ and TGFβ was near to each other. The A1AR, which was colocalized with CD34 partly, was also upregulated in DN patients. In WT-DN mice, obvious albuminuria and renal pathological leisure were observed. In A1AR−/− DN mice, more severe renal tubular interstitial fibrosis and more extracellular matrix deposition were observed, with lower CD34 expression and pronounced increase of PDGFRβ. In HK2 cells, high glucose stimulated the epithelial-mesenchymal transition (EMT) process, which was inhibited by A1AR agonist. Conclusion A1AR played a critical role in protecting the tubulointerstitial fibrosis process in DN by regulation of the peritubular microenvironment.
Highlights
Diabetic nephropathy (DN), the leading cause of end-stage renal disease (ESRD) [1], manifests with a progressive increase in proteinuria, with the deposition of extracellular matrix (ECM) components and subsequent glomerulosclerosis and tubulointerstitial fibrosis
As the major pathological changes and the crucial role in the progression of diabetic nephropathy (DN) [2], renal fibrosis is triggered by high glucose, which destroyed the stability of the renal peritubular microenvironment
Immunohistochemical semiquantitative analysis showed that the expression of CD34 was lower in DN patients (Figure 1(a)), as well as the higher expression of PDGFRβ in DN patients, compared to glomerular minor lesion (GML) patients (Figures 1(b) and 1(c))
Summary
Diabetic nephropathy (DN), the leading cause of end-stage renal disease (ESRD) [1], manifests with a progressive increase in proteinuria, with the deposition of extracellular matrix (ECM) components and subsequent glomerulosclerosis and tubulointerstitial fibrosis. As the major pathological changes and the crucial role in the progression of DN [2], renal fibrosis is triggered by high glucose, which destroyed the stability of the renal peritubular microenvironment. We previously observed that adenosine A1 receptor (A1AR) had a protective role in proximal tubular megalin loss associated with albuminuria in diabetic nephropathy (DN). The location and expression of CD34, PDGFRβ, and A1AR were detected in kidney tissue samples from DN patients by immunofluorescent and immunohistochemical staining. Human renal proximal tubular epithelial cells (HK2) were cultured in medium containing high glucose and A1AR agonist as well as antagonist. In A1AR-/- DN mice, more severe renal tubular interstitial fibrosis and more extracellular matrix deposition were observed, with lower CD34 expression and pronounced increase of PDGFRβ. A1AR played a critical role in protecting the tubulointerstitial fibrosis process in DN by regulation of the peritubular microenvironment
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