Kale Ajinath, Sankrityayan Himanshu, Anders Hans-Joachim, Gaikwad Anil Bhanudas
Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Pilani, Rajasthan, India.
Division of Nephrology, Department of Internal Medicine IV, University Hospital of the Ludwig Maximilians University of Munich, Munich, Germany.
Nephrol Dial Transplant. 2023 Mar 31;38(4):819-825. doi: 10.1093/ndt/gfab340.
Klotho is a transmembrane anti-ageing protein that exists in three forms, i.e. α-Klotho, β-Klotho and γ-Klotho, with distinct organ-specific expression and functions in the body. Here we focus on α-Klotho (hereafter Klotho), abundantly expressed by the distal and proximal convoluted tubules of the kidney. A significant decline in systemic and renal Klotho levels is a new hallmark for kidney disease progression. Emerging research portrays Klotho as a promising diagnostic and therapeutic target for diabetic and non-diabetic kidney disease. Even so, the underlying mechanisms of Klotho regulation and the strategies to restore its systemic and renal levels are still lacking. Angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers are the current standard of care for kidney diseases, but the molecular mechanisms for their nephroprotective action are still ambiguous. Moreover, endoplasmic reticulum (ER) stress also plays a crucial role in kidney disease progression. Few studies have claimed that the renin-angiotensin-aldosterone system (RAAS) has a direct relation with ER stress generation and vice versa in kidney disease. Interestingly, RAAS and ER stress modulation are associated with Klotho regulation in kidney disease. Here we focus on how the RAAS and ER stress connect with Klotho regulation in kidney disease. We also discuss Klotho and ER stress in an alliance with the concept of haemodynamic and metabolic overload in kidney disease. In addition, we highlight novel approaches to implement Klotho as a therapeutic target via RAAS and ER stress modulation for the treatment of diabetic and non-diabetic kidney diseases.
klotho是一种跨膜抗衰老蛋白，以三种形式存在，即α-klotho、β-klotho和γ-klotho，在体内具有不同的器官特异性表达和功能。在这里，我们重点关注α-klotho（以下简称klotho），它由肾脏的远曲小管和近曲小管大量表达。全身和肾脏klotho水平的显著下降是肾脏疾病进展的一个新标志。新出现的研究将klotho描绘为糖尿病和非糖尿病肾病有前景的诊断和治疗靶点。即便如此，klotho调节的潜在机制以及恢复其全身和肾脏水平的策略仍然缺乏。血管紧张素转换酶抑制剂和/或血管紧张素受体阻滞剂是目前肾脏疾病的标准治疗方法，但其肾脏保护作用的分子机制仍不明确。此外，内质网（ER）应激在肾脏疾病进展中也起着关键作用。很少有研究声称肾素-血管紧张素-醛固酮系统（RAAS）与肾脏疾病中ER应激的产生直接相关，反之亦然。有趣的是，RAAS和ER应激调节与肾脏疾病中的klotho调节有关。在这里，我们重点关注RAAS和ER应激在肾脏疾病中如何与klotho调节相关联。我们还结合肾脏疾病中的血流动力学和代谢过载概念讨论klotho和ER应激。此外，我们强调通过调节RAAS和ER应激将klotho作为治疗靶点用于治疗糖尿病和非糖尿病肾病的新方法。
