Research Progress on the Mechanism of Klotho Protein in Protecting Renal Function after Transplantation

I. Molecular Structure and Biological Characteristics of Klotho Protein

Klotho protein is a product encoded by the anti-aging gene Klotho, which was discovered in 1997 in a salt-sensitive hypertensive mouse model. The Klotho gene in both humans and mice is located on chromosome 13. Klotho protein exists in two isoforms: membrane-bound and secreted. The membrane-bound Klotho is a single-pass transmembrane protein composed of 1,012 amino acids, primarily expressed in the distal tubules of the kidneys. It serves as a specific co-receptor for fibroblast growth factor-23 (FGF-23) and participates in the regulation of phosphate excretion and calcium metabolism. The secreted Klotho is produced through alternative splicing of the membrane-bound Klotho and is mainly distributed in the blood. It contains the KL1 functional domain but lacks transmembrane and intracellular structures. Secreted Klotho acts as a humoral regulatory factor, exerting various cytoprotective functions such as anti-aging, anti-apoptosis, anti-oxidative stress, and anti-inflammatory responses.

II. Expression and Secretion of Klotho Protein in the Kidneys

Klotho protein is expressed in various tissues of humans and rodents, including the kidneys, choroid plexus of the brain, pituitary gland, parathyroid glands, pancreas, ovaries, testes, and placenta, with the highest expression levels observed in the distal tubule epithelial cells of the kidneys. The kidneys are the primary source of circulating Klotho protein. Bilateral nephrectomy or knockout of the Klotho gene in renal cells significantly reduces serum Klotho levels. Circulating Klotho protein can be transported from the basolateral membrane to the apical brush border of proximal tubule epithelial cells via transcytosis and is eventually secreted into the tubular lumen and excreted in the urine. The half-life of exogenous Klotho protein is significantly prolonged in the serum of anephric animals, suggesting that the kidneys play a crucial role in the clearance of circulating Klotho and are the main organs regulating its levels and mediating its biological effects.

III. Role of Klotho Protein in Renal Aging

The kidneys are one of the organs most susceptible to aging, and the Klotho gene, which is highly expressed in the kidneys, has anti-aging functions. Klotho gene knockout mice exhibit a multisystem phenotype similar to human aging, while overexpression of Klotho can inhibit aging and extend lifespan in mice. Studies have shown that Klotho expression in the kidneys gradually decreases during aging, and low Klotho expression is commonly observed in aging-related kidney diseases. Klotho protein exerts its anti-aging effects by downregulating telomerase activity and increasing telomere length, thereby delaying renal cell senescence. Additionally, Klotho protein participates in the regulation of phosphate metabolism. Its deficiency can impair the ability of FGF-23 to regulate phosphate homeostasis, leading to hyperphosphatemia. Overexpression of Klotho can reverse high phosphate-induced vascular smooth muscle cell calcification by inhibiting the Wnt7b/β-catenin pathway. Therefore, Klotho protein may serve as a potential therapeutic target for preventing renal aging.

IV. Protective Role of Klotho Protein in Renal Ischemia-Reperfusion Injury

Ischemia-reperfusion injury is an unavoidable pathophysiological process in kidney transplantation and is a significant cause of acute and chronic renal injury post-transplantation. Multiple studies have confirmed that ischemia-reperfusion injury reduces Klotho protein expression in the kidneys, while exogenous Klotho administration or increased expression can ameliorate ischemia-reperfusion-related renal injury. Overexpression of the Klotho gene enhances the resistance of mouse kidneys to ischemia-reperfusion injury, lowers pathological scores of renal injury, and promotes renal function recovery. Mechanistically, Klotho protein alleviates inflammatory responses by inhibiting the NF-κB signaling pathway, reduces oxidative stress, decreases apoptosis, and upregulates autophagy flux to exert renal protective effects. Furthermore, Klotho protein can enhance endothelial cell resistance to complement-dependent cytotoxicity and upregulate the expression of anti-inflammatory mediators.

V. Predictive Value of Klotho Protein for Transplanted Kidney Function

Clinical studies have shown that patients with acute kidney injury exhibit downregulated Klotho protein expression in the kidneys, and the extent of this downregulation correlates with the severity of renal injury. In allogeneic kidney transplantation, serum Klotho levels in recipients are significantly lower than those in healthy volunteers. Research has found that serum Klotho levels in older donors are associated with short-term post-transplant renal function recovery in recipients, suggesting that Klotho protein may serve as a potential biomarker for assessing transplanted kidney injury. Patients with delayed graft function exhibit significantly reduced Klotho protein expression in the transplanted kidneys, and serum Klotho levels remain low for up to two years post-transplantation, indicating that Klotho deficiency may be related to chronic allograft dysfunction secondary to delayed graft function. Moreover, elevated urinary Klotho protein levels in the early post-transplant period may serve as a new indicator for evaluating early tubular injury.

VI. Klotho Protein and Immunosuppressant Nephrotoxicity

Cyclosporine and tacrolimus are commonly used first-line immunosuppressants in kidney transplantation, but their nephrotoxicity can lead to decreased renal function in transplanted kidneys. Animal experiments have demonstrated that continuous cyclosporine administration induces macrophage infiltration in renal tissues, increases inflammatory factor expression, and is accompanied by reduced renal function and downregulated Klotho protein levels. Exogenous Klotho protein can ameliorate these effects and significantly lower serum creatinine and blood urea nitrogen levels. Mechanistic studies have revealed that Klotho protein may improve cyclosporine-induced renal inflammation by upregulating PDLIM2 expression and inhibiting the NF-κB pathway, as well as attenuate cyclosporine-induced renal fibrosis by inhibiting the epithelial-mesenchymal transition process. In tacrolimus-related renal injury, Klotho treatment can activate lysosomal function, enhance autophagy clearance, and upregulate superoxide dismutase expression while inhibiting oxidative stress through negative regulation of the PI3K/Akt pathway.

VII. Which Manufacturers Provide Klotho Protein?

Nanjing UA-Bio Technology Co., Ltd. has independently developed "Klotho Protein, Human", a high-quality recombinant protein reagent specifically designed for research on anti-aging mechanisms, metabolic regulation, and renal protection. This product is a human-derived Klotho protein, a transmembrane protein with β-glucuronidase activity that regulates various growth factor signaling pathways (e.g., FGF, Wnt, IGF-1) and participates in calcium-phosphate metabolism, oxidative stress resistance, and aging delay. It provides a stable and reliable standardized tool for research in aging biology, metabolic disease mechanisms, and drug development.

Nanjing UA-Bio Technology Co., Ltd. is dedicated to providing cutting-edge, high-quality core reagents and tools for immunology, cell therapy, and innovative drug development. For detailed technical parameters, validation data, or specific application inquiries regarding "Klotho Protein, Human" (Catalog No.: UA040033), please feel free to contact us.