Université de Paris, PARCC, Inserm, Paris, France.
Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Kidney Int. 2021 Jul;100(1):90-106. doi: 10.1016/j.kint.2021.02.024. Epub 2021 Mar 3.
The strong predictive value of proteinuria in chronic glomerulopathies is firmly established as well as the pathogenic role of angiotensin II promoting progression of glomerular disease with an altered glomerular filtration barrier, podocyte injury and scarring of glomeruli. Here we found that chronic angiotensin II-induced hypertension inhibited autophagy flux in mouse glomeruli. Deletion of Atg5 (a gene encoding a protein involved autophagy) specifically in the podocyte resulted in accelerated angiotensin II-induced podocytopathy, accentuated albuminuria and glomerulosclerosis. This indicates that autophagy is a key protective mechanism in the podocyte in this condition. Angiotensin-II induced calpain activity in podocytes inhibits autophagy flux. Podocytes from mice with transgenic expression of the endogenous calpain inhibitor calpastatin displayed higher podocyte autophagy at baseline that was resistant to angiotensin II-dependent inhibition. Also, sustained autophagy with calpastatin limited podocyte damage and albuminuria. These findings suggest that hypertension has pathogenic effects on the glomerular structure and function, in part through activation of calpains leading to blockade of podocyte autophagy. These findings uncover an original mechanism whereby angiotensin II-mediated hypertension inhibits autophagy via calcium-induced recruitment of calpain with pathogenic consequences in case of imbalance by calpastatin activity. Thus, preventing a calpain-mediated decrease in autophagy may be a promising new therapeutic strategy for nephropathies associated with high renin-angiotensin system activity.
蛋白尿在慢性肾小球疾病中有很强的预测价值，血管紧张素 II 促进肾小球疾病进展的致病作用也已得到确立，其作用机制为改变肾小球滤过屏障、足细胞损伤和肾小球瘢痕形成。在这里，我们发现慢性血管紧张素 II 诱导的高血压抑制了小鼠肾小球中的自噬流。特异性在足细胞中缺失 Atg5（编码参与自噬的蛋白质的基因）导致加速的血管紧张素 II 诱导的足细胞病变、加重白蛋白尿和肾小球硬化。这表明自噬是这种情况下足细胞中的一种关键保护机制。血管紧张素 II 诱导的足细胞钙蛋白酶活性抑制自噬流。来自转基因组内钙蛋白酶抑制剂钙蛋白酶抑制剂表达的小鼠的足细胞在基础水平显示出更高的自噬，对血管紧张素 II 依赖性抑制具有抗性。此外，持续的自噬与钙蛋白酶抑制剂一起限制了足细胞损伤和白蛋白尿。这些发现表明，高血压对肾小球的结构和功能具有致病作用，部分原因是通过钙依赖性募集钙蛋白酶激活，导致足细胞自噬受阻。这些发现揭示了一种原始机制，即血管紧张素 II 介导的高血压通过钙诱导的钙蛋白酶募集抑制自噬，而钙蛋白酶抑制剂的活性失衡则会产生致病后果。因此，预防钙蛋白酶介导的自噬减少可能是与高肾素-血管紧张素系统活性相关的肾病的一种有前途的新治疗策略。
