Effect of KW-3902, a novel adenosine A1 receptor antagonist, on sodium-dependent phosphate and glucose transport by the rat renal proximal tubular

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.

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Effects of KW-3902, an adenosine A1-receptor antagonist, on contrast media-induced renal vasoconstriction in anesthetized dogs.

The Japanese Journal of Pharmacology ◽

10.1016/s0021-5198(19)46818-2 ◽

1995 ◽

Vol 67 ◽

pp. 213

Author(s):

Tsuyoshi Yamagata ◽

Hideaki Kusaka ◽

Akira karasawa

Keyword(s):

Contrast Media ◽

Receptor Antagonist ◽

Adenosine A1 Receptor ◽

Renal Vasoconstriction ◽

Adenosine A1 ◽

Anesthetized Dogs ◽

A1 Receptor

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Upregulated renal adenosine A1 receptors augment PKC and glucose transport but inhibit proliferation

AJP Renal Physiology ◽

10.1152/ajprenal.1996.270.2.f263 ◽

1996 ◽

Vol 270 (2) ◽

pp. F263-F274 ◽

Cited By ~ 1

Author(s):

R. Coulson ◽

P. S. Proch ◽

R. A. Olsson ◽

C. E. Chalfant ◽

D. R. Cooper

Keyword(s):

Cell Proliferation ◽

Protein Kinase ◽

Glucose Uptake ◽

Glucose Transport ◽

Adenosine Receptor ◽

Adenosine A1 Receptor ◽

Receptor Antagonists ◽

Caffeine Treatment ◽

Adenosine A1 ◽

A1 Receptor

Adenosine A1 receptor densities were increased in cultured LLC-PK1 and OK cells by chronic treatment with the adenosine receptor antagonists 1,3,7-trimethylxanthine (caffeine, 1 mM) and 1,3-dimethyl-8-cyclopentylxanthine [cyclopentyltheophylline (CPT), < or = 0.4 mM], respectively. The A1 receptor number per cell was increased twofold by 10-day treatments with 1 mM caffeine or 0.1 mM CPT, and the sodium-coupled glucose uptake was augmented twofold by 1 mM caffeine and sevenfold by 0.1 microM CPT (higher doses of CPT were progressively less stimulatory). Glucose uptake was blocked by acute (2-h) treatment with CPT, adenosine deaminase, or calphostin C. Caffeine (1 mM) or CPT (> or = 0.1 mM) inhibited cell proliferation for the first 10 days, then cell growth assumed a normal proliferative rate despite continued presence of antagonist. Cytosolic protein kinase C (PKC) beta-isoform immunoactivity and PKC-beta II mRNA were elevated at least twofold during 10 days of 0.1 mM CPT or 1 mM caffeine treatment. The sustained elevation in sodium-glucose symport and PKC activity observed with adenosine receptor antagonists was similar to acute (2-h) effects of the adenosine A1 agonist R(-)-N6-phenylisopropyladenosine (R-PIA, 0.1-1 microM). Moreover, cell proliferation was increased by adenosine (0.1 microM R-PIA), whereas Na-K-adenosinetriphosphatase activity was unaltered with chronic antagonist or acute adenosine treatments. Caffeine treatment may have some non-adenosine A1 receptor-mediated actions, because it slightly (30%) augmented protein kinase A activity. It is concluded that chronic exposure of proximal tubule cells to caffeine or CPT augments PKC and sodium-glucose transport but retards cell proliferation mainly via adenosine A1 receptor-mediated mechanisms.

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