Inflammation-Induced Klotho Deficiency: A Possible Key Driver of Chronic Kidney Disease Progression

Yan Liang,1 Qi Zhang,1 Jing-Rong Qian,2 Sha-Sha Li,3 Qi-Feng Liu1,2 1Gusu School, Nanjing Medical University, The First People’s Hospital of Kunshan, Kunshan, Jiangsu, 215300, People’s Republic of China; 2Department of Nephrology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, Jiangsu, 215300, People’s Republic of China; 3Clinical Research and Laboratory Centre, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, Jiangsu, 215300, People’s Republic of ChinaCorrespondence: Sha-Sha Li, Email [email protected] Qi-Feng Liu, Email [email protected]: 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.Keywords: inflammation, Klotho, chronic kidney disease, epigenetics, non-epigenetics, kidney fibrosis