Renal and extrarenal actions of Klotho

Abstract

Klotho is a single-pass transmembrane protein highly expressed in the kidney. Membrane Klotho protein acts as a co-receptor for fibroblast growth factor-23. Its extracellular domain is shed from the cell surface and functions as an endocrine substance that exerts multiple renal and extrarenal functions. An exhaustive review is beyond the scope and length of this article; thus, only effects with pertinence to mineral metabolism and renoprotection are highlighted here. Klotho participates in mineral homeostasis via interplay with other calciophosphoregulatory hormones (parathyroid hormone, fibroblast growth factor-23, and 1,25-[OH]2 vitamin D3) in kidney, bone, intestine, and parathyroid gland. Klotho also may be involved in acute and chronic kidney disease development and progression. Acute kidney injury is a temporary and reversible state of Klotho deficiency and chronic kidney disease is a sustained state of systemic Klotho deficiency. Klotho deficiency renders the kidney more susceptible to acute insults, delays kidney regeneration, and promotes renal fibrosis. In addition to direct renal effects, Klotho deficiency also triggers and aggravates deranged mineral metabolism, secondary hyperparathyroidism, vascular calcification, and cardiac hypertrophy and fibrosis. Although studies examining the therapeutic effect of Klotho replacement were performed in animal models, it is quite conceivable that supplementation of exogenous Klotho and/or up-regulation of endogenous Klotho production may be a viable therapeutic strategy for patients with acute or chronic kidney diseases.

Figure 1. Physiologic roles of Klotho on solute channels and transporters and vitamin D metabolism in the kidney

Klotho is prominently expressed in distal convoluted tubules (DCT), and less in the proximal convoluted tubules (PCT). In PCT, membrane Klotho at the basolateral side functions as coreceptor of FGFRs and drive FGF23 signal transduction to inhibit NaPi cotransporters (NaPi: 2a/c and Pit2) and to suppress cyp27β1 encoding for 1-hydroxylase, and to stimulate cyp24α1 encoding for 24-hydoxylase. The role of Klotho in the cytoplasm of renal tubules is unclear. Whether membrane Klotho at luminal side inhibits NaPi cotransporters (2a/c and Pit2) in an autocrine mode is not known (dash line). In DCT, membrane Klotho at basolateral side functions as coreceptor of FGFRs to induce FGF23 signal transduction. What intermediate(s) are released from DCT and how intermediate(s) affect on PCT in paracrine mode is not known. One possible candidate is Klotho release from the DCT to act on the PCT. Whether membrane Klotho at luminal side directly regulates TRPV5 in autocrine mode is unknown. Soluble Klotho in luminal urine derived from either blood or urine exerts regulatory action on NaPi cotransporters in PCT; and on TRPV5 in DCT. Ca: calcium ion; DCT: distal convoluted tubule; FGF23: fibroblast growth factor; FGFR: FGF receptor; NaPi cotransporter: sodium-phosphate dependent cotransporter; PCT: proximal convoluted tubule; Pi: phosphate; TRPV5: transient receptor potential ion channel 5; 1,25 VD₃: 1,25-(OH)₂ vitamin D₃, Dash line: suspected action.

Figure 2. Proposed physiological role of Klotho in mineral metabolism and pathophysiologic consequences of Klotho deficiency in CKD

Left panel: In the setting of normal kidney function with normal Klotho levels, Klotho may suppress FGF23 production and release from the bone. But there is no data to date to prove direct effect of Klotho on FGF23 production in the bone. Klotho functions as coreceptor of FGFR to allow FGF23 to suppress PTH production and release from parathyroid. PTH stimulates and increases plasma levels of FGF23 and 1,25 VD₃. Increased 1,25 VD₃ further stimulates FGF23, and directly and indirectly suppresses PTH levels. Increased 1,25 VD₃ also stimulates Klotho production in the kidney. Taken together, through several negative or positive feedback loops, Klotho functions as both a phosphate and calcium regulatory hormone to directly or indirectly suppress PTH, 1,25 VD₃ and FGF23 production and release. The final outcome of Klotho’s action on the kidney is to prevent renal Pi retention and to prevent renal Ca loss. Right panel: In CDK and ESRD, the network is deranged (red arrows). Renal Klotho is decreased followed by decrease in plasma Klotho. The down-regulation of Klotho increases FGF23 production via unknown mechanism, which in turn suppresses 1,25 VD₃ production in the kidney. Whether low plasma Klotho renders parathyroid gland resistant to the suppressive effect of FGF23 on PTH production is not proven. However, decreased FGFR1/3 and Klotho expression in the uremic parathyroid gland could make the gland resistant to FGF23, and triggers or/and promotes secondary hyperparathyroidism. Low plasma Ca also participates in SHPT development. Hyperphosphatemia amplifies the high FGF23 and PTH, and low Klotho in the blood. The high plasma PTH, Pi and FGF23, and low plasma 1,25 VD₃ and Klotho in concert contribute to development of complications such as metabolic bone disease, secondary hyperparathyroidism, cardiomyopathy, and vascular calcification. Dash line: unproven putative roles of Klotho. Ca: ion calcium; CKD: chronic kidney disease; ESRD: End-stage renal disease; FGFR: FGF receptor; PTH: parathyroid hormone; Pi: phosphate; 1,25 VD₃: 1,25-(OH)₂ vitamin D₃