Blockade of the Adenosine A3 Receptor Attenuates Caspase 1 Activation in Renal Tubule Epithelial Cells and Decreases Interleukins IL-1β and IL-18 in Diabetic Rats

Garrido, Wallys; Jara, Claudia; Torres, Ángelo; Suárez, Raibel; Cappelli, Claudio; Oyarzún, Carlos; Quezada, Claudia; Martin, R. H.

doi:10.3390/ijms20184531

Cited by 21 publications

(23 citation statements)

References 58 publications

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“…However, our results are in line with more recent studies implicating the adenosine A 3 receptor in renal fibrosis. Indeed, molecules with targeted adenosine A 3 antagonistic activity are being advocated for their renal anti-fibrotic effects [ 54 ] including in diabetic nephropathy [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

Adenosine A2A and A3 Receptors as Targets for the Treatment of Hypertensive-Diabetic Nephropathy

et al. 2020

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Diabetic nephropathy (DN) and hypertension are prime causes for end-stage renal disease (ESRD) that often coexist in patients, but are seldom studied in combination. Kidney adenosine levels are markedly increased in diabetes, and the expression and function of renal adenosine receptors are altered in experimental diabetes. The aim of this work is to explore the impact of endogenous and exogenous adenosine on the expression/distribution profile of its receptors along the nephron of hypertensive rats with experimentally-induced diabetes. Using spontaneously hypertensive (SHR) rats rendered diabetic with streptozotocin (STZ), we show that treatment of SHR-STZ rats with an agonist of adenosine receptors increases A2A immunoreactivity in superficial glomeruli (SG), proximal tubule (PCT), and distal tubule (DCT). Differently, treatment of SHR-STZ rats with a xanthinic antagonist of adenosine receptors decreases adenosine A3 immunoreactivity in SG, PCT, DCT, and collecting duct. There is no difference in the immunoreactivity against the adenosine A1 and A2B receptors between the experimental groups. The agonist of adenosine receptors ameliorates renal fibrosis, probably via A2A receptors, while the antagonist exacerbates it, most likely due to tonic activation of A3 receptors. The reduction in adenosine A3 immunoreactivity might be due to receptor downregulation in response to prolonged activation. Altogether, these results suggest an opposite regulation exerted by endogenous and exogenous adenosine upon the expression of its A2A and A3 receptors along the nephron of hypertensive diabetic rats, which has a functional impact and should be taken into account when considering novel therapeutic targets for hypertensive-diabetic nephropathy.

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Section: Discussionmentioning

confidence: 99%

Adenosine A2A and A3 Receptors as Targets for the Treatment of Hypertensive-Diabetic Nephropathy

et al. 2020

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“…Serum and kidney levels of interleukin-1β (IL-1β) are increased in DN patients and participate in the progression of DN 8 . Tumour necrosis factor-α (TNFα) is overexpressed in the serum of diabetic patients, which increases glomerular vasoconstriction and the filtration rate 9 .…”

Section: Introductionmentioning

confidence: 99%

The CREB/KMT5A complex regulates PTP1B to modulate high glucose-induced endothelial inflammatory factor levels in diabetic nephropathy

Huang

Wang

et al. 2021

Cell Death Dis

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Diabetic nephropathy (DN) is the primary microvascular complication of diabetes mellitus and may result in end-stage renal disease. The overproduction of various inflammatory factors is involved in the pathogenesis of DN. Protein tyrosine phosphatase 1B (PTP1B) modulates the expression of a series of cytokines and nuclear factor kappa B (NF-κB) activity. cAMP response element-binding protein (CREB) and lysine methyltransferase 5A (KMT5A) have been reported to participate in the maintenance of a healthy endothelium. In the present study, we hypothesise that CREB associates with KMT5A to modulate PTP1B expression, thus contributing to high glucose-mediated glomerular endothelial inflammation. Our analyses revealed that plasma inflammatory factor levels, glomerular endothelial p65 phosphorylation and PTP1B expression were increased in DN patients and rats. In vitro, high glucose increased endothelial inflammatory factor levels and p65 phosphorylation by augmenting PTP1B expression in human umbilical vein endothelial cells (HUVECs). Moreover, high glucose decreased CREB and KMT5A expression. CREB overexpression and KMT5A overexpression both inhibited high glucose-induced PTP1B expression, p65 phosphorylation and endothelial inflammatory factor levels. si-CREB- and sh-KMT5A-induced p65 phosphorylation and endothelial inflammatory factor levels were reversed by si-PTP1B. Furthermore, CREB was associated with KMT5A. Mechanistic research indicated that CREB and histone H4 lysine 20 methylation (H4K20me1, a downstream target of KMT5A) occupy the PTP1B promoter region. sh-KMT5A augmented PTP1B promoter activity and activated the positive effect of si-CREB on PTP1B promoter activity. Our in vivo study demonstrated that CREB and KMT5A were downregulated in glomerular endothelial cells of DN patients and rats. In conclusion, CREB associates with KMT5A to promote PTP1B expression in vascular endothelial cells, thus contributing to hyperglycemia-induced inflammatory factor levels in DN patients and rats.

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“…3 The expression of interleukin-1β (IL-1β) increases in the serum and kidney of DN patients, and closely takes part in the progression of DN. 4 Excessive levels of tumor necrosis factor-α (TNF-α) can also be detected in the serum of diabetic patients, enhancing glomerular vasoconstriction and filtration rate. 5 The up-regulation of mononuclear chemotactic protein-1 (MCP-1), which participates in renal injury, is also correlated with the mechanism of DN.…”

Section: Introductionmentioning

confidence: 99%

<p>Wogonin Ameliorates Renal Inflammation and Fibrosis by Inhibiting NF-κB and TGF-β1/Smad3 Signaling Pathways in Diabetic Nephropathy</p>

Zheng¹,

Zhu²,

Lei³

et al. 2020

DDDT

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Introduction: Diabetic nephropathy (DN) has become an increasing threat to health, and inflammation and fibrosis play important roles in its progression. Wogonin, a flavonoid, has been proven to suppress inflammation and fibrosis in various diseases, including acute kidney injury. This study aimed at investigating the effect of wogonin on diabetes-induced renal inflammation and fibrosis. Materials and Methods: Streptozotocin (STZ)-induced diabetic mouse models received gavage doses of wogonin (10, 20, and 40 mg/kg) for 12 weeks. Metabolic indices from blood and urine and pathological damage of glomerulus in the diabetic model were assessed. Glomerular mesangial cells SV40 were cultured in high glucose (HG) medium containing wogonin at concentrations of 1.5825, 3.125, and 6.25 μg/mL for 24 h. Inflammation and fibrosis indices were evaluated by histopathological, Western blotting, and PCR analyses. Results: Wogonin treatment ameliorated albuminuria and histopathological lesions in diabetic mice. Inflammatory cytokines, such as monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and related signaling pathway NF-κB were downregulated after the administration of wogonin in vivo and in vitro. Furthermore, wogonin reduced the expression of extracellular matrix (ECM), including fibronectin (FN), collagen IV (Col-IV), α-smooth muscle actin (α-SMA), and transforming growth factor-β1 (TGF-β1) in the kidneys of diabetic mice and HG-induced mesangial cells. Moreover, the inhibition of TGF-β1/Smad3 pathway might be responsible for these changes. Conclusion: Wogonin may ameliorate renal inflammation and fibrosis in diabetic nephropathy by inhibiting the NF-κB and TGF-β1/Smad3 signaling pathways.

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Blockade of the Adenosine A3 Receptor Attenuates Caspase 1 Activation in Renal Tubule Epithelial Cells and Decreases Interleukins IL-1β and IL-18 in Diabetic Rats

Cited by 21 publications

References 58 publications

Adenosine A2A and A3 Receptors as Targets for the Treatment of Hypertensive-Diabetic Nephropathy

Adenosine A2A and A3 Receptors as Targets for the Treatment of Hypertensive-Diabetic Nephropathy

The CREB/KMT5A complex regulates PTP1B to modulate high glucose-induced endothelial inflammatory factor levels in diabetic nephropathy

<p>Wogonin Ameliorates Renal Inflammation and Fibrosis by Inhibiting NF-κB and TGF-β1/Smad3 Signaling Pathways in Diabetic Nephropathy</p>

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