Megalin-mediated albumin endocytosis in renal proximal tubules is involved in the antiproteinuric effect of angiotensin II type 1 receptor blocker in a subclinical acute kidney injury animal model,Biochimica et Biophysica Acta (BBA) - General Subjects

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Megalin-mediated albumin endocytosis in renal proximal tubules is involved in the antiproteinuric effect of angiotensin II type 1 receptor blocker in a subclinical acute kidney injury animal model
Biochimica et Biophysica Acta (BBA) - General Subjects ( IF 2.8 ) Pub Date : 2021-06-16 , DOI: 10.1016/j.bbagen.2021.129950
Diogo B Peruchetti ₁ , Paulo F R Barahuna-Filho ₂ , Rodrigo P Silva-Aguiar ₃ , Thiago P Abreu ₁ , Christina M Takiya ₃ , Jie Cheng ₄ , Ana Acacia S Pinheiro ₅ , Liudmila Cebotaru ₆ , William B Guggino ₆ , Celso Caruso-Neves ₇

Affiliation

Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Department of Physiology, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA.
Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Instituto de Ciências Biomédicas, Universidade Estadual do Ceará, Fortaleza, Brazil.
Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Department of Ophthalmology, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA.
Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Rio de Janeiro Innovation Network in Nanosystems for Health - NanoSAUDE/FAPERJ, Rio de Janeiro, Brazil.
Department of Physiology, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA.
Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Rio de Janeiro Innovation Network in Nanosystems for Health - NanoSAUDE/FAPERJ, Rio de Janeiro, Brazil; Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa, INCT-Regenera, Conselho Nacional de Desenvolvimento Científico e Tecnológico/MCTIC, Rio de Janeiro, Brazil.

Background

Tubule-interstitial injury (TII) is one of the mechanisms involved in the progression of renal diseases with progressive proteinuria. Angiotensin II (Ang II) type 1 receptor blockers (ARBs) have been successfully used to treat renal diseases. However, the mechanism correlating treatment with ARBs and proteinuria is not completely understood. The hypothesis that the anti-proteinuric effect of losartan is associated with the modulation of albumin endocytosis in PT epithelial cells (PTECs) was assessed.

Methods

We used a subclinical acute kidney injury animal model (subAKI) and LLC-PK1 cells, a model of PTECs.

Results

In subAKI, PT albumin overload induced TII development, measured by: (1) increase in urinary lactate dehydrogenase and γ-glutamyltranspeptidase activity; (2) proteinuria associated with impairment in megalin-mediated albumin reabsorption; (3) increase in luminal and interstitial space in tubular cortical segments. These effects were avoided by treating the animals with losartan, an ARB. Using LLC-PK1 cells, we observed that: (1) 20 mg/mL albumin increased the secretion of Ang II and decreased megalin-mediated albumin endocytosis; (2) the effects of Ang II and albumin were abolished by 10⁻⁸ M losartan; (3) MEK/ERK pathway is the molecular mechanism underlying the Ang II-mediated inhibitory effect of albumin on PT albumin endocytosis.

Conclusion

Our results show that PT megalin-mediated albumin endocytosis is a possible target during the treatment of renal diseases patients with ARB.

General significance

The findings obtained in the present work represents a step forward to the current knowledge on about the role of ARBs in the treatment of renal disease.

中文翻译：

Megalin介导的肾近端小管白蛋白内吞作用与血管紧张素II 1型受体阻滞剂在亚临床急性肾损伤动物模型中的抗蛋白尿作用有关

背景

肾小管间质损伤 (TII) 是与进行性蛋白尿的肾脏疾病进展相关的机制之一。血管紧张素 II (Ang II) 1 型受体阻滞剂 (ARB) 已成功用于治疗肾脏疾病。然而，与 ARB 治疗和蛋白尿相关的机制尚不完全清楚。评估了氯沙坦的抗蛋白尿作用与 PT 上皮细胞 (PTEC) 中白蛋白内吞作用的调节相关的假设。

方法

我们使用了亚临床急性肾损伤动物模型 (subAKI) 和 LLC-PK1 细胞，一种 PTEC 模型。

结果

在 subAKI 中，PT 白蛋白超载诱导 TII 发展，通过以下方式测量：(1) 尿乳酸脱氢酶和 γ-谷氨酰转肽酶活性的增加；(2) 与巨蛋白介导的白蛋白重吸收障碍相关的蛋白尿；(3)管状皮质节段管腔和间质空间增加。用氯沙坦（一种 ARB）治疗动物可以避免这些影响。使用 LLC-PK1 细胞，我们观察到： (1) 20 mg/mL 白蛋白增加了 Ang II 的分泌并减少了巨蛋白介导的白蛋白内吞作用；(2) 10 ^-8 M 氯沙坦可消除Ang II和白蛋白的作用；(3) MEK/ERK通路是Ang II介导的白蛋白抑制PT白蛋白内吞作用的分子机制。