Hajare Aditya Dipakrao, Dagar Neha, Gaikwad Anil Bhanudas
Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan, 333031, India.
Mol Biomed. 2025 Mar 22;6(1):19. doi: 10.1186/s43556-025-00253-y.
Klotho, initially introduced as an anti-aging protein, is expressed in the brain, pancreas, and most prominently in the kidney. The two forms of Klotho (membrane-bound and soluble form) have diverse pharmacological functions such as anti-inflammatory, anti-oxidative, anti-fibrotic, tumour-suppressive etc. The membrane-bound form plays a pivotal role in maintaining kidney homeostasis by regulating fibroblast growth factor 23 (FGF 23) signalling, vitamin D metabolism and phosphate balance. Klotho deficiency has been linked with significantly reduced protection against various kidney pathological phenotypes, including diabetic kidney disease (DKD), which is a major cause of chronic kidney disease leading to end-stage kidney disease. Owing to the pleiotropic actions of klotho, it has shown beneficial effects in DKD by tackling the complex pathophysiology and reducing kidney inflammation, oxidative stress, as well as fibrosis. Moreover, the protective effect of klotho extends beyond DKD in other pathological conditions, including cardiovascular diseases, alzheimer's disease, cancer, inflammatory bowel disease, and liver disease. Therefore, this review summarizes the relationship between Klotho expression and various diseases with a special emphasis on DKD, the distinct mechanisms and the potential of exogenous Klotho supplementation as a therapeutic strategy. Future research into exogenous Klotho could unravel novel treatment avenues for DKD and other diseases.
klotho最初作为一种抗衰老蛋白被发现，它在大脑、胰腺中均有表达，在肾脏中的表达最为显著。klotho的两种形式（膜结合型和可溶性形式）具有多种药理功能，如抗炎、抗氧化、抗纤维化、肿瘤抑制等。膜结合型klotho通过调节成纤维细胞生长因子23（FGF 23）信号传导、维生素D代谢和磷酸盐平衡，在维持肾脏内环境稳定方面发挥关键作用。klotho缺乏与对各种肾脏病理表型的保护作用显著降低有关，包括糖尿病肾病（DKD），而糖尿病肾病是导致终末期肾病的慢性肾病的主要原因。由于klotho具有多效性作用，它通过解决复杂的病理生理学问题以及减轻肾脏炎症、氧化应激和纤维化，在糖尿病肾病中显示出有益效果。此外，klotho的保护作用在糖尿病肾病之外的其他病理状况下也有体现，包括心血管疾病、阿尔茨海默病、癌症、炎症性肠病和肝病。因此，本综述总结了klotho表达与各种疾病之间的关系，特别强调了糖尿病肾病、不同的机制以及外源性补充klotho作为一种治疗策略的潜力。对外源性klotho的未来研究可能会为糖尿病肾病和其他疾病揭示新的治疗途径。
