Exploring the Therapeutic Potency of Systemic Klotho Deficiency Treatment

Treatment of Systemic Klotho Deficiency

A cardiologist from Japan accidentally disrupted the promoter of the klotho genes in 1997, resulting in a phenotype that mimicked premature aging. The gene is named after the Greek goddess who spins life’s threads. In 2005, this same investigator performed the opposite experiment, showing that overexpression of klotho transgenically in mice extended life. This put Klotho back in the spotlight, and sparked a flurry of antiaging research. A number of findings changed the landscape. Klotho, a transmembrane single-pass protein, is expressed primarily in the kidney. However, its extracellular domain, after being cleaved with proteases, is secreted as a soluble Klotho into circulation [3] ; the kidney therefore supplies the body soluble Klotho. Multiple preclinical studies using diverse models have shown that both chronic and acute kidney disease are caused by renal and systemic klotho deficiencies [3], which includes human CKD. Klotho’s relationship with kidney disease goes beyond a simple biomarker. Klotho restoration improved renal dysfunction, and other extrarenal complications both in acute [4] settings and chronic settings. Klotho supplementation is now a therapeutic option. How should Klotho supplementation be administered?

Several methods have been successfully used to increase systemic Klotho in rodents (Fig. 1). First attempt was to insert klotho transgenically into the mouse genome [2]. This technique, while extremely useful for proof-of concept in animals, is not currently applicable to patients. In both acute [5] and chronic [4] settings, recombinant Klotho was successfully used in the lab to prevent AKI, accelerate AKI recovery and present and retard AKI-to CKD transition. It also ameliorated extrarenal complication [4]. The use of recombinant Klotho proteins is a more direct and practical method for translating to human therapeutics.


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