Liang Yan, Zhang Qi, Qian Jing-Rong, Li Sha-Sha, Liu Qi-Feng
Gusu School, Nanjing Medical University, The First People's Hospital of Kunshan, Kunshan, Jiangsu, 215300, People's Republic of China.
Department of Nephrology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, Jiangsu, 215300, People's Republic of China.
Int J Gen Med. 2025 May 11;18:2507-2520. doi: 10.2147/IJGM.S513497. eCollection 2025.
Chronic kidney disease (CKD) is influenced by inflammation, a critical factor in its progression. However, the underlying mechanism through which inflammation contributes to CKD is still obscure. The Klotho protein, which is predominantly found in the kidneys, is known for its protective functions, including anti-inflammatory, anti-aging, antioxidant, and anti-fibrotic effects. A myriad of studies have suggested that inflammation in CKD leads to a decrease in Klotho expression, diminishing Klotho protection capabilities and exacerbating kidney damage, thereby promoting CKD progression. These findings suggest that Klotho deficiency could be a crucial link between inflammation and CKD progression. However, the mechanism regarding their relationship is still unclear. The reduction in Klotho due to inflammation may be attributed to epigenetic mechanisms, such as DNA methylation, histone deacetylation, transcription factor, microRNA (miRNA) regulation and long non-coding RNA (lncRNA) regulation or non-epigenetic factors, such as endoplasmic reticulum (ER) stress and ER-associated degradation (ERAD), which affect Klotho protein metabolism. Through these pathways, inflammation triggers a decrease in Klotho expression, further driving CKD progression. Notably, Klotho also exerts a strong anti-inflammatory effect by inhibiting key inflammatory factors and pathways, suggesting that there is intricate crosstalk between inflammatory factors and Klotho in CKD. This review highlights how inflammation suppresses the expression of Klotho and further contributes to the development and exacerbation of CKD. By focusing on the interplay between inflammation and Klotho, the present review provides novel potential therapeutic strategies such as correcting epigenetic and non-epigenetic abnormalities for treating CKD by targeting this specific axis.
慢性肾脏病（CKD）受炎症影响，炎症是其进展的关键因素。然而，炎症导致CKD的潜在机制仍不清楚。主要在肾脏中发现的Klotho蛋白以其保护功能而闻名，包括抗炎、抗衰老、抗氧化和抗纤维化作用。大量研究表明，CKD中的炎症导致Klotho表达降低，削弱了Klotho的保护能力，加剧了肾脏损伤，从而促进了CKD的进展。这些发现表明，Klotho缺乏可能是炎症与CKD进展之间的关键联系。然而，它们之间关系的机制仍不清楚。炎症导致的Klotho减少可能归因于表观遗传机制，如DNA甲基化、组蛋白去乙酰化、转录因子、微小RNA（miRNA）调节和长链非编码RNA（lncRNA）调节，或非表观遗传因素，如内质网（ER）应激和内质网相关降解（ERAD），这些都会影响Klotho蛋白代谢。通过这些途径，炎症引发Klotho表达降低，进一步推动CKD进展。值得注意的是，Klotho还通过抑制关键炎症因子和途径发挥强大的抗炎作用，这表明在CKD中炎症因子与Klotho之间存在复杂的相互作用。本综述强调了炎症如何抑制Klotho的表达，并进一步促进CKD的发生和加重。通过关注炎症与Klotho之间的相互作用，本综述提供了新的潜在治疗策略，如通过针对这一特定轴纠正表观遗传和非表观遗传异常来治疗CKD。
