The effect of A1 adenosine receptor in diabetic megalin loss with caspase-1/IL18 signaling
| Autor: | Lubin Xu, Limeng Chen, Yubin Wen, Xiaoxiao Shi, Ying Ma, Robert Faulhaber-Walter, Xiaoyan Peng, Linfeng Zou, Dongli Tian, Yumo Zhao |
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| Rok vydání: | 2019 |
| Předmět: |
Agonist
medicine.medical_specialty medicine.drug_class 030209 endocrinology & metabolism 030204 cardiovascular system & hematology urologic and male genital diseases Diabetic nephropathy 03 medical and health sciences 0302 clinical medicine Internal medicine Internal Medicine medicine Pharmacology Kidney business.industry Cubilin Streptozotocin medicine.disease Adenosine receptor Endocrinology medicine.anatomical_structure Albuminuria Interleukin 18 medicine.symptom business medicine.drug |
| Zdroj: | Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 12:1583-1596 |
| ISSN: | 1178-7007 |
| DOI: | 10.2147/dmso.s215531 |
| Popis: | Purpose In our previous study, exacerbation of albuminuria was observed in A1 adenosine receptor knockout (A1AR-/-) mice with diabetic nephropathy (DN), but the mechanism was unclear. Here, we investigated the relationship of megalin loss and albuminuria, to identify the protective effect of A1AR in megalin loss associated albuminuria by inhibiting pyroptosis-related caspase-1/IL-18 signaling of DN. Methods We successfully collected DN patients' samples and built diabetes mice models induced by streptozotocin. Megalin, cubilin, and A1AR expression were detected in kidney tissue samples from DN patients and mice through immunohistochemical and immunofluorescent staining. A1AR, caspase-1, interleukin-18 (IL-18) expression were analyzed using Western blotting in wild-type and A1AR-/- mice. Human renal proximal tubular epithelial cells (PTC) were cultured with high glucose to observe the effect of A1AR agonist and antagonist on caspase-1/IL-18 and megalin injury. Results The loss of megalin, co-localized with A1AR at PTC, was associated with the level of albuminuria in diabetic patients and mice. The injury of megalin-cubilin was accompanied with the A1AR upregulation (1.30±0.1 vs 0.98±0.2, P=0.042), the caspase-1 (1.33±0.1 vs 1.0±0.2, P=0.036), and IL-18 (1.26±0.2 vs 0.96±0.2, P=0.026) signaling activation in mice with DN. More severe pathological injury, 24 hrs urine albumin excretion (170.8±4.1 μg/d vs 132.0±2.9 μg/d vs 17.9±2.8 μg/d, P |
| Databáze: | OpenAIRE |
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