Klotho in Clinical Nephrology Diagnostic and Therapeutic Implications

CJASN ePress. Published on July 22, 2020 as doi: 10.2215/CJN.02840320 Klotho in Clinical Nephrology Diagnostic and Therapeutic Implications Javier A. Neyra,1,2,3 Ming Chang Hu,1,2 and Orson W. Moe1,2,4 Abstract aKlotho (called Klotho here) is a membrane protein that serves as the coreceptor for the circulating hormone fibroblast growth factor 23 (FGF23). Klotho is also cleaved and released as a circulating substance originating 1Charles and Jane Pak primarily from the kidney and exerts a myriad of housekeeping functions in just about every organ. The vital role of Center for Mineral Klotho is shown by the multiorgan failure with genetic deletion in rodents, with certain features reminiscent of Metabolism and Clinical Research, human disease. The most common causes of systemic Klotho deficiency are AKI and CKD. Preclinical data on Klotho Dallas, Texas biology have advanced considerably and demonstrated its potential diagnostic and therapeutic value; however, 2Department of multiple knowledge gaps exist in the regulation of Klotho expression, release, and metabolism; its target organs; and Internal Medicine, mechanisms of action. In the translational and clinical fronts, progress has been more modest. Nonetheless, Klotho University of Texas Southwestern Medical has potential clinical applications in the diagnosis of AKI and CKD, in prognosis of progression and extrarenal Center, Dallas, Texas complications, and finally, as replacement therapy for systemic Klotho deficiency. The overall effect of Klotho in 3Division of clinical nephrology requires further technical advances and additional large prospective human studies. Nephrology, Bone and CJASN 16: ccc–ccc, 2021. doi: https://doi.org/10.2215/CJN.02840320 Mineral Metabolism, Department of Internal Medicine, University of Kentucky, Introduction Soluble Klotho protein is also detected in cerebrospinal Lexington, Kentucky aKlotho (referred here as Klotho) was serendipitously fluid and urine. 4Department of discovered in 1997 by Kuro-o et al. (1) as a gene linked Klotho is a pleiotropic protein with multifaceted Physiology, University to aging. This gene was named Klotho after the goddess of Texas Southwestern functions relevant to distinct biology and pathobi- Medical Center, who spins the thread of life to govern human lifespan, ology in multiple organs and tissues. Klotho is an Dallas, Texas working with two other goddesses of fate, Lachesis inhibitor of apoptosis, fibrosis, and cell senescence who measures the spun thread from Klotho’s spindle and is an inducer of autophagy (13–16). In this Correspondence: and Atropos who ends the life by cutting the thread (2). review, we discuss its potential clinical application Dr. Javier A. Neyra or Kuro-o et al. (1) observed that Klotho hypomorphic in nephrology, with emphasis on diagnostic and ther- Dr. Ming Chang Hu, mice exhibited a multiorgan failure syndrome re- Charles and Jan Pak apeutic utility. Center for Mineral sembling premature aging, including short lifespan, Metabolism and disturbed mineral metabolism, and multiple organ Clinical Research, degeneration or failure, such as infertility, arterio- Physiology of Klotho University of Texas sclerosis, cardiomyopathy, ectopic calcification, skin Klotho Expression and Metabolism Southwestern Medical fi Center, 5323 Harry atrophy, osteoporosis, and emphysema. Later, both Klotho is highly expressed in the kidney, speci - Hines Boulevard, human (3) and rat (4) Klotho genes were cloned with cally in the distal tubules and, to a lesser extent, in the Dallas, TX 75390- high homology in amino acid sequences with the proximal tubules (17). Klotho is expressed in other 8856. Email: javier. mouse. Subsequently, two paralogous genes were organs, such as the brain, pancreas, and parathyroid [email protected] or discovered and termed bKlotho (5) and gKlotho (6) to glands (1). The Klotho gene encodes a single-pass 130- ming-chang.hu@ utsouthwestern.edu distinguish them from the first Klotho gene, which was kD transmembrane protein that consists of two renamed aKlotho. The a- and bKlotho proteins have extracellular domains (Kl1 and Kl2), a transmembrane known biologic roles, but the function of gKlotho is domain, and a short cytoplasmic tail (Figure 1). The still elusive (7,8). In this manuscript, we only focus on extracellular domain of transmembrane Klotho is aKlotho (Klotho). cleaved at the juxtamembrane region and between Klotho is mostly expressed in the kidney as a trans- Kl1 and Kl2 by proteases (18–20). A secreted form of membrane protein. In membrane-bound form, Klotho Klotho from an alternatively spliced transcript has serves as a coreceptor for fibroblast growth factor 23 been proposed, but the data are not conclusive (3,21). (FGF23) in conjunction with fibroblast growth factor The spliced Klotho transcript possibly undergoes receptors (FGFRs) (9) (Figure 1). The extracellular nonsense-mediated mRNA decay and is not trans- domain of transmembrane Klotho is also cleaved by lated to protein (22). The cleaved Klotho is released proteases and released from the kidney into circula- into the circulation and is known as soluble Klotho tion, both as a full-length protein or as Kl1 and Kl2 (17,22). Soluble Klotho acts as an endocrine or para- fragments (10,11). These circulating forms of Klotho crine factor affecting multiple organs, such as the protein are collectively called “soluble” Klotho (Figure 1). kidney, bone, brain, heart, lungs, and endothelium www.cjasn.org Vol 16 January, 2021 Copyright © 2021 by the American Society of Nephrology 1 2 CJASN Figure 1. | Overview of Klotho protein. (A) Fibroblast growth factor 23 (FGF23) engages the fibroblast growth factor receptor (FGFR)-Klotho coreceptor complex that triggers cellular signaling. (B) Transmembrane Klotho with its Kl1 and Kl2 domains and the generation of soluble circulating Klotho by secretases (ADAM10 and ADAM17). (C) Structure of FGFR1c, Klotho, and FGF23 (one molecule each) as determined by Chen et al. (12). RXXR motif, proteolytic cleavage motif. Cont. (23–29). Soluble Klotho suppresses FGF23 production in Klotho is also expressed in the choroid plexus of the physiologic concentrations (Figure 2), but it can increase brain (1). Klotho-deficient mice display central nervous FGF23 expression in the bone (28) or act as a nonenzymatic system lesions including hypomyelination, synaptic loss, scaffold protein that enhances FGF23 signaling on the basis and behavioral impairments such as dementia and cog- of in vitro data in very high, nonphysiologic concentrations nitive deficits (38). Klotho deficiency in the brain impairs (12). Soluble Klotho is not filtered at the glomerulus, but it blood barrier and promotes immune-mediated central translocates across the kidney tubules, from the basolateral nervous system disorders (39). CKD is associated with to the luminal side, and is excreted in the urine (17). Klotho depression and cognitive impairment (40). Low Klotho in expression is downregulated during acute kidney dis- cerebrospinal fluid was confirmed in Alzheimer disease ease and CKD. (41). Low soluble Klotho in CKD may conceivably contrib- ute to central nervous system dysfunction, although there is no evidence to date of Klotho deficiency in cerebrospinal Klotho and Mineral Metabolism fluid or brain in CKD. Klotho decreases kidney phosphate reabsorption by acting as a coreceptor for FGF23 binding to FGFR1 (30) (Figure 1). Soluble Klotho also directly promotes the Cardiovascular Disease internalization and degradation of the NaPi2a cotrans- A novel risk factor of cardiovascular disease in CKD is fi porter in the kidney proximal tubules contributing to soluble Klotho de ciency (42,43). Hyperphosphatemia phosphate excretion (31). Klotho may also be a suppressor and low soluble Klotho associate with more severe cardiac fi of vitamin D and FGF23 production (32) because Klotho- hypertrophy and brosis. Interestingly, elevated levels of deficient mice exhibit higher CYP27B1 gene (33) and FGF23 FGF23 were associated with pathologic cardiac remodeling fi production (1) (Figure 2). only if Klotho de ciency was also present (34). However, exogenous FGF23, independent of Klotho, induced cardiac hypertrophy through FGFR4-mediated PLC-g signaling activation in cardiac myocytes (43,44). Klotho, Klotho in Disease States independent of FGF23, was postulated to protect the CKD heart against cardiac hypertrophy through inhibition Klotho expression in the kidney and soluble Klotho in the of transient receptor potential channel-6 activity in car- blood and urine are decreased in animals and humans with diomyocytes (45). Klotho supplementation also protects CKD from a variety of etiologies, including glomerular and against indoxyl sulfate–mediated cardiac hypertrophy tubulointerstitial diseases (32). Because the kidneys are in mice (46). the primary source of soluble Klotho, circulating soluble Klotho expectedly declines as CKD progresses (Figure 3). Decreased Klotho expression in CKD is not simply due AKI to loss of viable tissue but can be attributable to hyper- AKI is a syndrome with a myriad of inflammatory phosphatemia (34) and hypermethylation or deacetylation cytokines such as TNF-a and TNF-like weak inducer of of the Klotho gene promoter by inflammatory cytokines or apoptosis, which downregulate Klotho expression in the uremic toxins, such as indoxyl sulfate (35,36). Similarities kidney through NF-kB activation in murine AKI (47). of clinical features, including short lifespan, cardiac remodel- Similarly, in other inflammatory conditions such as inflam- ing, vascular

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