Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2016;101:257-310.
doi: 10.1016/bs.vh.2016.02.007. Epub 2016 Mar 24.

αKlotho and Chronic Kidney Disease

Affiliations
Free PMC article
Review

αKlotho and Chronic Kidney Disease

J A Neyra et al. Vitam Horm. .
Free PMC article

Abstract

Alpha-Klotho (αKlotho) protein is encoded by the gene, Klotho, and functions as a coreceptor for endocrine fibroblast growth factor-23. The extracellular domain of αKlotho is cleaved by secretases and released into the circulation where it is called soluble αKlotho. Soluble αKlotho in the circulation starts to decline in chronic kidney disease (CKD) stage 2 and urinary αKlotho in even earlier CKD stage 1. Therefore soluble αKlotho is an early and sensitive marker of decline in kidney function. Preclinical data from numerous animal experiments support αKlotho deficiency as a pathogenic factor for CKD progression and extrarenal CKD complications including cardiac and vascular disease, hyperparathyroidism, and disturbed mineral metabolism. αKlotho deficiency induces cell senescence and renders cells susceptible to apoptosis induced by a variety of cellular insults including oxidative stress. αKlotho deficiency also leads to defective autophagy and angiogenesis and promotes fibrosis in the kidney and heart. Most importantly, prevention of αKlotho decline, upregulation of endogenous αKlotho production, or direct supplementation of soluble αKlotho are all associated with attenuation of renal fibrosis, retardation of CKD progression, improvement of mineral metabolism, amelioration of cardiac function and morphometry, and alleviation of vascular calcification in CKD. Therefore in rodents, αKlotho is not only a diagnostic and prognostic marker for CKD but the enhancement of endogenous or supplement of exogenous αKlotho are promising therapeutic strategies to prevent, retard, and decrease the comorbidity burden of CKD.

Keywords: Cardiovascular disease; Chronic kidney disease; FGF23; Hyperphosphatemia; Klotho; Uremic cardiomyopathy; Vascular calcification.

Figures

Fig. 1
Fig. 1
Source of circulatory αKlotho. αKlotho protein is expressed in a few organs, but the kidney is a main resource of circulating αKlotho under physiological conditions. The contribution of parathyroid gland and brain is not clear. Both renal proximal (PT) and distal tubules (DT) express membrane αKlotho protein and may also produce a secreted αKlotho protein which only contains kl1 domain and is directly secreted into the blood circulation. Extracellular domain of membrane αKlotho-containing kl1 and kl2 repeats is shed and cleaved by α and β-secretases, and released into the blood circulation.
Fig. 2
Fig. 2
Circulating and local renal factors involved in the reduction of αKlotho expression in the kidney. In acute and chronic kidney disease, a variety of circulating factors including disturbed mineral metabolism, and accumulation of indoxyl sulfate and proinflammatory cytokines (left panel), can downregulate renal αKlotho expression. On the other hand, the elevation of reactive oxygen species, Ang II, and inflammatory cytokines in the diseased kidney can also downregulate renal αKlotho expression (right panel). Epigenetic modulation of αKlotho promoter via hypermethylation and deacetylation can reduce αKlotho expression and contribute to αKlotho deficiency in chronic kidney disease.
Fig. 3
Fig. 3
Proposed physiological role of αKlotho in mineral metabolism and pathophysiological consequences of αKlotho deficiency in CKD. In the setting of normal kidney function with normal αKlotho levels (left panel), αKlotho may suppress FGF23 production and release from the bone. But there is no direct evidence to prove it. αKlotho functions as coreceptor of FGFR to allow FGF23 to suppress PTH production and release from parathyroid gland. PTH stimulates and increases plasma levels of FGF23 and 1,25-(OH)2-vitamin D3. Increased 1,25-(OH)2-vitamin D3 further stimulates FGF23, and directly and indirectly suppresses PTH levels. Increased 1,25-(OH)2-vitamin D3 also stimulates αKlotho production in the kidney. Taken together, through several negative- or positive-feedback loops, αKlotho functions as both a phosphate and calcium regulatory hormone to directly or indirectly suppress PTH, 1,25-(OH)2-vitamin D3, and FGF23 production and release. αKlotho's action on the kidney is to prevent renal Pi retention and to prevent renal Ca loss. In CKD and ESRD (right panel), the network is deranged (red arrows). Renal αKlotho is decreased followed by decrease in plasma αKlotho. The downregulation of αKlotho increases FGF23 production via unknown mechanism, which in turn suppresses 1,25-(OH)2-vitamin D3 production in the kidney. Whether low plasma αKlotho renders parathyroid gland resistant to the suppressive effect of FGF23 on PTH production is not proven. However, decreased FGFR1/3 and αKlotho expression in the uremic parathyroid gland could make the gland resistant to FGF23, and triggers and/or promotes secondary hyperparathyroidism (SHPT). Low plasma Ca also participates in SHPT development. Hyperphosphatemia amplifies the high FGF23 and PTH levels, and low αKlotho levels in the blood. The high plasma PTH, Pi, and FGF23, and low plasma 1,25-(OH)2-vitamin D3 and αKlotho in concert contribute to the development of complications such as metabolic bone disease, SHPT, cardiomyopathy, and vascular calcification. Dash line: unproven putative roles of αKlotho. Ca, ion calcium; CKD, chronic kidney disease; ESRD, end-stage renal disease; FGFR, FGF receptor; Pi, phosphate; PTH, parathyroid hormone; SHPT, secondary hyperparathyroidism; 1,25-VD3, 1,25-(OH)2-vitamin D3.
Fig. 4
Fig. 4
Risk factors for uremic cardiomyopathy and proposed mechanisms of attenuation of pathological cardiac remodeling by αKlotho. αKlotho deficiency is a novel risk factor for uremic cardiomyopathy. Soluble αKlotho deficiency is an intermediate mediator of the pathological cardiac remodeling observed in CKD. Experimental αKlotho overexpression (Tg-Kl) suppressed phosphorylation of Smad2/3 and Erk, which are known to be involved in uremic cardiac fibrosis. Furthermore, αKlotho may protect the heart against stress-induced cardiac hypertrophy by inhibiting TRPC-6 channel-mediated abnormal Ca2+ signaling in the heart or against uremic solute indoxyl sulfate-induced myocardial hypertrophy probably by suppressing NADPH oxidase Nox2/Nox4-derived reactive oxygen species production and its downstream signaling. CHF, congestive heart failure; Erk, extracellular signal-regulated kinase; LVH, left ventricular hypertrophy; MAPK, mitogen-activated protein kinases; Nox, NADPH oxidase; SCD, sudden cardiac death; TRPC-6, transient receptor potential canonical-6.
Fig. 5
Fig. 5
Proposed model of αKlotho as intermediate of endothelial cells (ECs)–vascular smooth muscle cells (VSMCs) cross talk. Left panel: Normal ECs–VSMCs cross talk. Normal ECs modulate VSMCs growth via release of growth factors (black line in left panel). NO, nitric oxide; PDGF, platelet-derived growth factor; PGI2, prostaglandin I2; VEGF, vascular endothelial growth factor. VEGF released from pericytes and/or VSMCs could also regulate endothelial cell. Right panel: In CKD, uremic toxins including high plasma Pi, damage ECs and induce release of growth factors, proinflammatory cytokines, and profibrotic factors, which exacerbate ECs injury and also induce VSMCs transition to osteoblast and promote vascular calcification in medial layer (red solid lines in right panel). Impaired ECs also directly contributes to vascular calcification through endo-osteoblast transition (green line in right panel). Whether dedifferentiated or damaged VSMCs could further modulate function of endothelial cells is speculative (red dash line in right panel). Central panel: αKlotho is a vascular protective protein. Whether resident aortic αKlotho protein in VSMCs functions in autocrine and/or paracrine mode to modulate VSMCs and/or ECs remains to be clarified (brown dash line in central panel). The mechanisms of how αKlotho is able to reach the VSMCs from the circulation and function as an endocrine factor remain to be defined (blue dash line in central panel). αKlotho, regardless of source, could increase NO production from ECs and NO consequently modulates VSMCs and ECs function in an autocrine mode (blue solid line in middle panel). αKlotho could protect EC from high phosphate and other uremic toxins and also attenuate oxidative stress and proinflammatory cytokines-induced cell senescence and apoptosis in VSMC (orange line in central panel). αKlotho also directly inhibits osteoblast transition induced by hyperphosphatemia and uremic milieu (orange line in central panel). Current experimental and clinical observations suggest that both ECs and VSMCs endothelium may be potential targets of soluble αKlotho to protect the vasculature from vascular calcification in CKD. ECs, endothelial cells; Pi, phosphorus; VSMCs, vascular smooth muscle cells.

Similar articles

See all similar articles

Cited by 7 articles

See all "Cited by" articles
Feedback