Potential application of klotho in human chronic kidney disease

Abstract

The extracellular domain of transmembrane alpha-Klotho (αKlotho, hereinafter simply called Klotho) is cleaved by secretases and released into the circulation as soluble Klotho. Soluble Klotho in the circulation starts to decline early in chronic kidney disease (CKD) stage 2 and urinary Klotho possibly even earlier in CKD stage 1. Therefore soluble Klotho could serve as an early and sensitive marker of kidney function decline. Moreover, preclinical animal data support Klotho deficiency is not just merely a biomarker, but a pathogenic factor for CKD progression and extrarenal CKD complications including cardiovascular disease and disturbed mineral metabolism. Prevention of Klotho decline, re-activation of endogenous Klotho production or supplementation of exogenous Klotho are all associated with attenuation of renal fibrosis, retardation of CKD progression, improvement of mineral metabolism, amelioration of cardiomyopathy, and alleviation of vascular calcification in CKD. Therefore Klotho is not only a diagnostic and/or prognostic marker for CKD, but the treatment of Klotho deficiency may be a promising strategy to prevent, retard, and decrease the burden of comorbidity in CKD.

Keywords: AKI; CKD; Klotho; Phosphate; Uremic cardiomyopathy; Vascular calcification; Vitamin D.

Figure 1. Source of soluble Klotho

The kidney is the main source of circulating Klotho under physiological conditions. Both renal proximal and distal tubules express membrane Klotho protein and may also produce a secreted Klotho protein through alternative splicing. The secreted Klotho only contains Kl1 domain and is directly secreted into the blood circulation. But its biologic function is not clear yet. Extracellular domain of membrane Klotho containing Kl1 and Kl2 repeats is shed and cleaved by secretases into either full extracellular domain or Kl1 repeat. Both cleaved Klotho fragments are present in the circulation. A few extra-renal organs including parathyroid gland and brain express Klotho protein as well, but their contribution to circulating Klotho in CKD/ESRD (dash line) remains to be confirmed.

Figure 2. Potential mechanisms of Klotho downregulation in CKD, and beneficial effects of soluble Klotho on CKD

Left panel: Loss of renal mass, over production of reactive oxygen species (ROS) as well as pro-inflammatory cytokines including tumor necrosis factor (TNF), interferon (IFN) and interleukin 1 (IL-1), dyslipidemia and hyperglycemia, and elevation of uremic toxins including indoxyl sulfate and p-cresyl sulfate may contribute to or participate in downregulation of renal Klotho. Furthermore, high serum phosphate and FGF23 as well as low serum 1,25-Vit.D₃ inhibit renal Klotho expression. Low serum 1,25-Vit.D₃ not only reduces Klotho expression, but also stimulates renin-aldosterone-angiotensin (RAA) system which further suppresses Klotho production. Middle panel: Reduced Klotho expression in the kidney would lead to endocrine Klotho deficiency in CKD. Low soluble Klotho promotes CKD progression to ESRD through impaired normal renal repair process and induction of maladaptive repair process. Right panel: Supplementation of soluble Klotho protein retards CKD progression through multiple biologic actions: (1) cytoprotection via anti-oxidation, reduction of cell senescence and apoptosis, and upregulation of autophagy, hence accelerating renal tubule regeneration; (2) correction of high serum phosphate and FGF23; (3) maintenance of peritubular capillary formation and function; and (4) inhibition of tubuloinsterstitial fibrosis.