Upstream and downstream regulators of Klotho expression in chronic kidney disease

Klotho is a critical protein that protects the kidney. Klotho is severely downregulated in chronic kidney disease (CKD), and its deficiency is implicated in the pathogenesis and progression of CKD. Conversely, an increase in Klotho levels results in improved kidney function and delays CKD progression, supporting the notion that modulating Klotho levels could represent a possible therapeutic strategy for CKD treatment. Nevertheless, the regulatory mechanisms responsible for the loss of Klotho remain elusive. Previous studies have demonstrated that oxidative stress, inflammation, and epigenetic modifications can modulate Klotho levels. These mechanisms result in a decrease in Klotho mRNA transcript levels and reduced translation, thus can be grouped together as upstream regulatory mechanisms. However, therapeutic strategies that aim to rescue Klotho levels by targeting these upstream mechanisms do not always result in increased Klotho, indicating the involvement of other regulatory mechanisms. Emerging evidence has shown that endoplasmic reticulum (ER) stress, the unfolded protein response, and ER-associated degradation also affect the modification, translocation, and degradation of Klotho, and thus are proposed to be downstream regulatory mechanisms. Here, we discuss the current understanding of upstream and downstream regulatory mechanisms of Klotho and examine potential therapeutic strategies to upregulate Klotho expression for CKD treatment.