Klotho and Kidney Disease: Research Status and Progress

Klotho, a recently discovered anti-aging gene, is primarily expressed in the kidneys (especially in distal tubule epithelial cells), the brain, and the parathyroid glands. It exists in both membrane-bound and secreted forms and demonstrates multiple biological functions closely related to kidney diseases, including anti-oxidative, anti-inflammatory, anti-apoptotic, anti-fibrotic, and anti-vascular calcification effects. As a result, Klotho is regarded as a novel renal protective protein. This article reviews the current research progress on Klotho in relation to diabetic kidney disease, renal fibrosis, chronic kidney disease, acute kidney injury, and vascular calcification, and offers perspectives on future research directions.

How does Klotho influence macrophage polarization in diabetic kidney disease (DKD)?

In diabetic kidney disease (DKD), albumin absorbed by renal tubular epithelial cells triggers inflammation and plays a key role in disease progression. Abnormal urinary albumin excretion has been identified as a major driver of DKD advancement. Existing studies have confirmed that extracellular vesicles (EVs) secreted by albumin-treated HK-2 cells can affect macrophage polarization, thereby accelerating DKD development. Recent findings suggest that targeting Klotho in macrophages may alleviate DKD progression by reducing inflammation. However, the exact mechanism by which Klotho regulates macrophage polarization remains unclear. Given that urinary EV-miR-199a-5p may reflect the inflammatory state of the kidney, future therapeutic strategies for DKD may involve blocking the transfer of EV miR-199a-5p from renal tubular cells to macrophages or specifically targeting macrophage Klotho.

Can Klotho serve as a non-invasive biomarker for renal fibrosis?

Renal fibrosis has long been a central focus in nephrology research. Currently, diagnosis relies on renal biopsy, an invasive procedure that cannot be easily repeated. There is a pressing clinical need to identify non-invasive biomarkers that allow dynamic monitoring of disease progression. Analysis of biomarkers in blood or urine may offer a promising alternative. Secreted Klotho protein, detectable in blood, urine, and cerebrospinal fluid, functions as a humoral factor with multiple biological roles—such as anti-inflammation, anti-oxidation, ion channel regulation in the kidneys, and inhibition of Wnt signaling, apoptosis, and senescence. Moreover, Klotho expression levels closely correlate with renal function, making it a potential novel biomarker for diagnosing kidney diseases.

Inhibiting the progression of renal fibrosis is a universal goal in nephrology. Recent studies highlight that acute kidney injury (AKI)-induced renal fibrosis is a key area of interest. Research indicates that reducing the methylation rate of the Klotho gene promoter in renal tissue can upregulate Klotho expression and alleviate post-AKI renal fibrosis, offering new insights for clinical treatment strategies.

What mechanisms underlie Klotho’s protective role in chronic kidney disease (CKD)?

Klotho is recognized as a renal protective factor, though its precise mechanisms are not fully elucidated. Possible pathways include anti-oxidative stress, anti-apoptosis, anti-aging, and regulation of vascular homeostasis. In patients with chronic kidney disease (CKD), Klotho expression is significantly reduced—a phenomenon also observed in other conditions characterized by premature vascular aging, such as hypertension and diabetes. Patients undergoing dialysis or with end-stage renal disease exhibit only 5%–15% of the normal Klotho expression levels. Animal studies have shown that α-Klotho plays a critical role in mitigating renal failure progression; its overexpression prevents renal medullary deterioration and cortical thinning. Several medications, including PPARγ agonists, angiotensin II type I receptor blockers, vitamin D receptor agonists (VDRAs), and rapamycin, have been shown to upregulate Klotho expression in both in vitro and in vivo models. Therefore, enhancing endogenous Klotho levels may represent a novel therapeutic strategy for CKD-related conditions.

How is Klotho expression altered in acute kidney injury (AKI)?

Acute kidney injury induces a severe but transient decline in Klotho expression in the kidneys and endocrine tissues. Studies in rodents have shown that blood and urinary Klotho levels decrease significantly during AKI. This reduction is among the earliest changes following kidney injury and is reversible upon recovery of renal function. This suggests that AKI represents a state of temporary Klotho deficiency, highlighting its potential role as both a diagnostic marker and a therapeutic target in acute renal damage.

What is the role of Klotho in vascular calcification?

Vascular calcification refers to the abnormal deposition of calcium-phosphate complexes (hydroxyapatite) in the vascular wall, including intimal and medial calcification. Medial calcification is commonly associated with CKD, aging, and diabetes. Patients with chronic renal failure experience accelerated and severe vascular calcification, leading increased vessel stiffness—a major cause of mortality among dialysis patients.

Studies have shown that soft tissue and vascular calcification are widespread in Klotho-deficient (Kl+/-) and wild-type mice with CKD, whereas Klotho-overexpressing transgenic mice with CKD are protected from calcification. Calcification primarily affects the aorta and kidneys, confirming that Klotho attenuates vascular calcification. Moreover, Klotho transgenic CKD mice do not develop hyperphosphatemia, suggesting that Klotho may promote urinary phosphate excretion—a possible mechanism through which it inhibits vascular calcification.

Summary and Outlook

In the near future, clinical testing of blood or urine Klotho levels may become widespread, providing critical information for the diagnosis of kidney and cardiovascular diseases. Therapeutically, Klotho is emerging as a promising new target for nephrology treatment. Strategies aimed at increasing endogenous Klotho or administering exogenous Klotho may hold significant potential for treating kidney diseases, vascular calcification, hyperphosphatemia, and other related conditions.