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Klotho in CKD and AKI

Klotho in CKD and AKI. Dr. CKD – Chronic Kidney Disease AKI – Acute Kidney Injury. Overview. Introduction Klotho in Nephrology Calcium and Phosphate metabolism Vascular and soft tissue calcification Klotho and FGF23 in CKD Klotho in AKI Conclusions. FGF – Fibroblast growth factor.

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Klotho in CKD and AKI

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  1. Klotho in CKD and AKI Dr CKD – Chronic Kidney Disease AKI – Acute Kidney Injury

  2. Overview • Introduction • Klotho in Nephrology • Calcium and Phosphate metabolism • Vascular and soft tissue calcification • Klotho and FGF23 in CKD • Klotho in AKI • Conclusions FGF – Fibroblast growth factor

  3. Introduction • Klotho • One of the three goddesses of the Moirae*, who in Greek mythology • Control the life (spins the thread of life) and destiny of everyone • She is the goddess who helps life to unfold, in contrast to • The (apoptotic) goddess Atropos, who cuts the thread of life *Moirae - any of the three Greek goddesses of fate or destiny

  4. Introduction • Klotho – medical science • Gene • Identified app. 13 years ago, by the Japanese group of Kuro-o et al.* • Named after Greek goddess, • As prolonging lifespan is probably the most important role of this ageing-suppressor gene *Nature 1997; 390: 45–51

  5. Introduction • Japanese researchers reported • Defect in Klotho gene expression in the mouse resulted in a syndrome that resembled • Human ageing, including • Short lifespan, infertility, arteriosclerosis, skin atrophy, osteoporosis and emphysema • The gene encoded a membrane protein that • Shared sequence similarity with the beta-glucosidase enzymes Nature 1997; 390: 45–51

  6. Introduction 7-week-old normal mouse (left) and a klotho mouse, an animal model that shows multiple phenotypes resembling human aging

  7. Introduction Ageing Research Reviews 2009;8:43–51

  8. Introduction • Japanese researchers observation • Led them to conclude that • The protein might function as part of a signalling pathway involved in the regulation of ageing and related diseases • One year later, • The same group isolated the human homologue of the Klotho gene and determined its structure Nature 1997; 390: 45–51 Biochem Biophys Res Commun 1998; 242: 626–630

  9. Introduction Ageing Research Reviews 2009;8:43–51

  10. Introduction Ageing Research Reviews 2009;8:43–51

  11. Introduction Ageing Research Reviews 2009;8:43–51

  12. Introduction • The Klotho gene encodes • Single-pass transmembrane protein • Belongs to a family 1 glycosidase • Expressed primarily in renal tubules (distal tubules) • Present in the circulation and urine Blood Cells Mol Dis 1998; 24: 83–100

  13. Why is Klotho of particular interest for nephrology? • Klotho is involved in the • Renal control of calcium, phosphate and vitamin D metabolism • Suppresses phosphate re-absorption in renal proximal tubule, by directly binding to FGF receptors • Regulates Ca2+ re-absorption in the distal convoluted tubule by • Stabilizing the TRPV5 Ca2+ channel in the plasma membrane Nephrol Dial Transplant 2007; 22: 1524–1526

  14. Why is Klotho of particular interest for nephrology? • Klotho • Inhibits renal 1-alpha 25 hydroxylase activity and thereby • Decreases circulating calcitriol levels • Therefore appears to • Synergize with the renal tubular effects of parathyroid hormone (PTH) on Ca2+ and phosphate transport, whereas • Antagonizes the stimulatory effect of PTH on calcitriol synthesis by the kidney Nephrol Dial Transplant 2007; 22: 1524–1526

  15. Effect of FGF23 plus Klotho on renal tubular re-absorption of • inorganic phosphate (iP) and synthesis of 1,25 dihydroxy vitamin D • (calcitriol). • FGF23 + Klotho act synergistically with PTH to reduce tubular iP re absorption. However, FGF23 + Klotho inhibit tubular calcitriol synthesis, in contrast to PTH which stimulates it • In end-stage renal disease (ESRD), the physiological inhibition of tubular iP re-absorption by both PTH and FGF23 + Klotho becomes ineffective. The concomitant increase in PTH secretion leads to excessive iP release from bone into the extracellular space. The clinical consequence is hyperphosphataemia. Nephrol Dial Transplant 2007; 22: 1524–1526

  16. Why is Klotho of particular interest for nephrology? • Klotho-deficient mice and FGF23-deficient mice have an identical phenotype including • Hyperphosphataemia, hypercalcaemia, elevated plasma calcitriol and vascular calcification, in addition to premature ageing • In contrast, over-expression of the Klotho gene • Extends the lifespan and increases resistance to oxidative stress Nephrol Dial Transplant 2007; 22: 1524–1526

  17. Why is Klotho of particular interest for nephrology? • These observations were highly suggestive of a close cooperation between Klotho and FGF23 and/or its receptor(s) Nephrol Dial Transplant 2007; 22: 1524–1526

  18. Function of Klotho Nephrol Dial Transplant 2007; 22: 1524–1526

  19. Regulation of FGF23 signaling by Klotho • The common phenotypes of Klotho and FGF23 overexpression and deletion, respectively, led to the postulate of a • Common signal transduction pathway • Kurosu et al.* showed that • Klotho protein directly bound to multiple FGFRs • The Klotho–FGFR complex bound to FGF23 with higher affinity than FGFR or Klotho alone *J Biol Chem 2006; 281: 6120–6123

  20. Regulation of FGF23 signaling by Klotho • Conversion by Klotho of canonical FGF receptor into FGF23-specific receptor Nephrol Dial Transplant 2007; 22: 1524–1526

  21. Regulation of FGF23 signaling by Klotho • Klotho functions as an obligatory coreceptor for FGF23 • Experimental studies have demonstrated convincingly that FGF23, in the absence of klotho, cannot exert its bioactivities • For instance, despite extremely high serum levels of FGF23 (about 2000-fold higher) in klotho ablated mice, FGF is unable to exert its phosphaturic effects in these mice Kidney Int. 2008 ; 74(5): 566–570.

  22. Regulation of FGF23 signaling by Klotho • The fact that FGF23 requires Klotho as a co-receptor explains • Why Klotho-deficient mice develop phenotypes identical with those observed in FGF23-deficient mice and • Why Klotho-deficient mice had extremely high serum FGF23 levels Nephrol Dial Transplant 2009;24: 1705–1708

  23. Regulation of FGF23 signaling by Klotho • Kidney-specific expression of Klotho explains why FGF23 can identify the kidney as its target organ among many other tissues that express multiple FGFR isoforms Nephrol Dial Transplant 2009;24: 1705–1708

  24. Klotho in Calcium metabolism Ageing Research Reviews 2009;8:43–51

  25. Pflugers Arch - Eur J Physiol 2010; 459:333–343

  26. 1,25(OH)2D being a major stimulus, which is feedback regulated by klotho via an inhibition of the 1-hydroxylase activity. Klotho has a significant impact on the Ca 2+ reabsorption via the epithelial Ca 2+ channel, TRPV5, in the distal convoluted and connecting tubules Klotho is produced in the kidneys and is reduced in chronic uraemia Mutations in the klotho gene and klotho deficiency have been related to the process of ageing, osteoporosis, rteriosclerosis, ectopic calcifications and skin atrophy Nephrol Dial Transplant 2006; 21: 1770–1772

  27. Klotho in Phosphate metabolism • The bone–kidney endocrine axis mediated by FGF23 and Klotho has emerged as an essential component in the regulation of phosphate homeostasis • When phosphate is in excess, FGF23 is secreted from bone and acts on the kidney where Klotho is expressed • As a phosphaturic hormone, FGF23 reduces the amount of sodium phosphate co-transporter type-2a (NaPi-2a) on the brush border membrane of proximal tubules, thereby promoting renal phosphate excretion Nephrol Dial Transplant 2009;24: 1705–1708

  28. Klotho in Phosphate metabolism • As a counter-regulatory hormone for vitamin D, FGF23 suppresses synthesis and promotes inactivation of 1,25- dihydroxyvitamin D3 in proximal tubules Nephrol Dial Transplant 2009;24: 1705–1708

  29. Phosphate regulation by klotho: Hypotheses. The first arrow starts from the intestine, where a reduced dietary phosphate intake diminishes serum phosphate concentration and leads to a decrease in PTH secretion, which physiologically reduces urinary phosphate excretion. In addition, to save phosphate, the renal action of FGF23 will decrease facilitating tubular phosphate reabsorption by the stimulation of sodium-dependent phosphate cotransporters (NPT2a and NPT2c). It will also facilitate the synthesis of 1,25(OH)2D3 in spite of low PTH levels. The increase in calcitriol levels stimulates sodium-dependent phosphate cotransporter type IIb expression and intestinal phosphate absorption. Then, to counteract the activation of these three phosphate-saving mechanisms and to avoid hyperphosphatemia, the renal synthesis of klotho is increased. This increase in renal klotho will facilitate the phosphaturic action of FGF23. Klotho binds to FGFR1(IIIc) and forms the specific FGF23 receptor. Furthermore, klotho negatively regulates the synthesis of 1,25(OH)2D3 by enabling FGF23 binding to its receptor and thereby its inhibitory effect on 1--hydroxylase activity. At the bone level, klotho could stimulate bone resorption and phosphate release by acting on TRPV5, which is a recently identified osteoclast function modulator. The increased levels of 1,25(OH)2D3 could also stimulate osteoclast differentiation and bone resorption and thereby phosphate release. It could also stimulate skeletal FGF23 synthesis to control further, at the renal level, any excessive increase in serum phosphate resulting from the activation of the prophosphatemic mechanisms. Abbreviations: PTH, parathyroid hormone; FGF23, fibroblast growth factor-23; TRPV5, epithelial calcium channel TRPV5 (transient receptor potential vallinoid-5). Kidney Int. 2007 Apr;71(8):730-7.

  30. The bone–kidney–parathyroid endocrine axes mediated by FGF23 and Klotho Active vitaminD(1,25-dihydroxyvitaminD3) binds to the vitamin Dreceptor (VDR) in osteocytes. The ligand-boundVDRforms a heterodimerwith a nuclear receptor RXRand transactivates the FGF23 gene expression. FGF23 secreted from bone acts on the Klotho–FGFR complex in kidney (the bone–kidney axis) and parathyroid gland (the bone–parathyroid axis). In kidney, FGF23 suppresses synthesis of active vitamin D by down-regulating expression of the Cyp27b1 gene and promotes its inactivation by up-regulating expression of the Cyp24 gene, thereby closing a negative feedback loop for vitamin D homeostasis. In the parathyroid gland, FGF23 suppresses production and secretion of PTH. Since PTH is a potent inducer of Cyp27b1 gene expression, suppression of PTH by FGF23 reduces expression of the Cyp27b1 gene as well as serum levels of 1,25-dihydroxyvitamin D3, which closes another long negative feedback loop for vitamin D homeostasis. Klotho and FGF23 are indispensable for the regulation of vitamin D metabolism because defects in either Klotho or FGF23 cause hypervitaminosis D. Nephrol Dial Transplant 2009;24: 1705–1708

  31. Overlay of the systemic phosphate homeostasis with the major players in the phosphate regulatory network and their functional interactions (-stimulation; inhibition) Laboratory Investigation 2009;89, 7–14

  32. Pflugers Arch - Eur J Physiol 2010; 459:333–343

  33. Klotho in Phosphate toxicity • Disruption of the bone–kidney endocrine axis mediated by Klotho and FGF23 results in hyperphosphataemia, hypercalcaemia and hypervitaminosis D associated with multiple ageing-like phenotypes • These observations have raised the possibility that toxicity of phosphate, calcium and/or vitamin D may be responsible for the premature ageing syndrome observed in Klotho- and FGF23-deficient mice

  34. Klotho in Phosphate toxicity • Recent epidemiological studies support the notion of ‘phosphate toxicity’ in humans • Serum phosphate levels were shown to positively correlate all-cause mortality risk, even when serum phosphate levels are within the normal range Circulation 2005; 112: 2627–2633

  35. Klotho in Phosphate toxicity • In addition, • Chronic kidney disease (CKD) patients with hyperphosphataemia (≥6.5 mg/dl) were reported to have higher risk for death resulting from several diseases including coronary artery disease than those with the lower serum phosphate levels (<6.5 mg/dl) J Am Soc Nephrol 2001; 12: 2131–2138

  36. Klotho in Vascular calcification • Both FGF23 and klotho ablated mice develop extensive vascular and soft tissue calcification • Inability to clear the required amount of phosphate by the kidney, due to the absence of FGF23-klotho activity, leads to • Increased serum accumulation of phosphate in these genetically modified mice, causing extensive calcification Kidney Int. 2008 ; 74(5): 566–570.

  37. Klotho in Vascular calcification • Serum calcium levels are also elevated in both FGF23and klotho ablated mice • Moreover, increased sodium phosphate co-transporter activity in both FGF23and klotho ablated mice increases renal phosphate reabsorption which in turn can facilitate calcification Kidney Int. 2008 ; 74(5): 566–570.

  38. Klotho in Vascular calcification • Wild-type mice with CKD had very low renal, plasma, and urinary levels of Klotho • In humans, authors observed a graded reduction in urinary Klotho starting at an early stage of CKD and progressing with loss of renal function J Am Soc Nephrol. 2011 Jan;22(1):124-36.

  39. Klotho in Vascular calcification • Despite induction of CKD, transgenic mice that overexpressed Klotho had preserved levels of Klotho, enhanced phosphaturia, better renal function, and much less calcification compared with wild-type mice with CKD J Am Soc Nephrol. 2011 Jan;22(1):124-36.

  40. Klotho in Vascular calcification • Conversely, Klotho-haplo insufficient mice with CKD had undetectable levels of Klotho, worse renal function, and severe calcification • The beneficial effect of Klotho on vascular calcification was a result of more than its effect on renal function and phosphatemia, suggesting a direct effect of Klotho on the vasculature J Am Soc Nephrol. 2011 Jan;22(1):124-36.

  41. Klotho in Vascular calcification • In vitro, Klotho suppressed Na(+)-dependent uptake of phosphate and mineralization induced by high phosphate and preserved differentiation in vascular smooth muscle cells • Klotho deficiency contributes to soft-tissue calcification in CKD J Am Soc Nephrol. 2011 Jan;22(1):124-36.

  42. Klotho in Vascular calcification • Klotho ameliorates vascular calcification by • Enhancing phosphaturia • Preserving glomerular filtration, and • Directly inhibiting phosphate uptake by vascular smooth muscle J Am Soc Nephrol. 2011 Jan;22(1):124-36.

  43. Klotho in Vascular calcification • Collectively, these observations bring new insights into our understanding of the roles of the FGF23 -klotho axis in the development of vascular and soft tissue calcification Kidney Int. 2008 ; 74(5): 566–570.

  44. Klotho and FGF23 in CKD • The National Kidney Foundation task force indicated that • The cardiovascular mortality of a 35-year-old patient on dialysis was equivalent to that of an 80-year-old healthy individual, rendering CKD to be the most potent accelerator of vascular senescence J Am Soc Nephrol 1998; 9: S31–S42

  45. Klotho and FGF23 in CKD • Furthermore, the American Heart Association announced in 2003* that • CKD should be included in the highest risk group for cardiovascular disease • Like Klotho-deficient mice, • CKD patients suffer vascular calcification and have elevated serum levels of FGF23 and phosphate • Importantly, Klotho expression is decreased in CKD patients** *Circulation 2003; 108: 2154–2169, **Biochem Biophys Res Commun 2001; 280: 1015–1020

  46. Klotho and FGF23 in CKD • These observations suggest that Klotho deficiency may contribute to pathophysiology of CKD • Of note, recent animal studies have shown that • Klotho functions as a renoprotective factor • Although the mechanism remains to be determined, over-expression of Klotho ameliorated progressive renal injury in mouse models of glomerulonephritis* and acute kidney injury** Nephrol Dial Transplant 2009;24: 1705–1708 *Proc Natl Acad Sci USA 2007; 104: 2331–2336 **Nephrol Dial Transplant 2005; 20: 2636–2645

  47. Klotho and FGF23 in CKD • Thus, decrease in Klotho expression potentially accelerates renal damage, leading to a deterioration spiral of Klotho expression and renal function • Because 1,25- dihydroxyvitamin D3 increases Klotho expression in kidney, vitamin D treatment may be useful for interrupting this vicious cycle Nephrol Dial Transplant 2009;24: 1705–1708

  48. Klotho and FGF23 in CKD • Epidemiological studies have identified high serum levels of phosphate and FGF23 as independent mortality risks in CKD patients • Importantly, serum FGF23 levels increase before serum phosphate levels increase during the progression of CKD suggesting that • Resistance to FGF23 may be one of the earliest changes in phosphate metabolism in CKD • Although the mechanism of FGF23 resistance is yet to be determined, it can be caused by a decrease in renal Klotho expression Nephrol Dial Transplant 2009;24: 1705–1708

  49. Klotho and FGF23 in CKD • Provided that serum FGF23 levels are a surrogate marker for renal Klotho expression levels, the fact that high serum FGF23 levels are associated with poor prognosis in patients undergoing dialysis • Suggests that low renal Klotho expression levels may be primarily responsible for the poor prognosis

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