Klotho: renal and extra-renal effects
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1 Klotho: renal and extra-renal effects Juan F. Navarro-González, MD, PhD, FASN Nephrology Service and Research Division University Hospital Nuestra Señora de Candalaria Santa Cruz de Tenerife. Spain
2 Klotho: the begining. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997, Nov 6;390: Kuro-o M, et al. Vascular calcification
3 The 2 K connection Kidney Phosphorus Klotho
4 Henning Brand, 1669 The discovery of phosphorus Joseph Wright
5 ALCHEMY, THE KIDNEY AND PHOSPHORUS Urine is boiled to obtain a thick syrup. Heating until it distils a reddish oil. Cooling the remaider material: a black spongy top and a bottom saline part. Discard the salt and mix the reddish oil with the black part. Heating the mixture vigorously for nearly a day. White smoke first and then an oily fluid. Finally you obtain a waxy white material that emits light in the darkness. Phosphorus that produces light
6 Phosphorus balance in normal physiology Total adult body stores g Net: mg The kidney is the main regulator of human phosphate homeostasis
7 Renal tubular phosphate reabsorption occurs through two families of sodium-phosphate co-transporters: NaPi-II and PIT-2 70% of P reabsorption
8 Classical view of phosphate regulation Parathyroid hormone and Vitamin D
9 Classical view of phosphate regulation Parathyroid hormone and Vitamin D Changes in dietary P induces Variations in renal P reabsorption Without changes in vitamin D and PTH Tumor induced osteomalacia X-linked hypop rickets Autosomal-dominant hypop rickets Altered P, normal PTH & Vit. D Phosphate regulation needed a specific hormone
10 Fibroblast growth factor 23
11 Implant of cells genetically modified to produce FGF23 resulted in: Reduction of serum P Increase in urinary P excretion
12
13 How FGF-23 works? Intracellular pathways
14 How FGF-23 works? Reduction of renal tubular P reabsorption Increased renal phosphate excretion NaPT2a 3Na + HPO 4 2- NaPT2c 2Na + HPO 4 2- Tubular lumen Renal tubular cell FGFR FGF-23
15 FGF23 needs a co-receptor Klotho Intracellular pathways
16 NPT2a 3Na + HPO 4 2- NPT2c 2Na + HPO 4 2- Renal tubular cell FGFR FGF-23 Klotho
17 Klotho FGF23 FGF receptor Klotho gene (13q12)
18 Renal actions of Klotho: - Phosphaturic effect (FGF23-dependent). - Phosphaturic effect (independent of FGF23).
19 Plasma levels Fractional excretion Renal expression of NaPi-2a Chang et al. FASEB J 2010
20 Renal actions of Klotho: - Phosphaturic effect (FGF23-dependent). - Phosphaturic effect (independent of FGF23). - Regulation of ion channels (calcium and potassium).
21 Calbindin and Transient Receptor Potential Vanilloid 5 & 6 Chang et al. Science 2005 Lu et al. NDT 2008
22 ROMK1
23 Renal actions of Klotho: - Phosphaturic effect (FGF23-dependent). - Phosphaturic effect (independent of FGF23). - Regulation of ion channels (calcium and potassium). - Regulation of Vitamin D.
24 Serum levels Renal expresssion of 1α-hydroxylase
25 Renal actions of Klotho: - Phosphaturic effect (FGF23-dependent). - Phosphaturic effect (independent of FGF23). - Regulation of ion channels (calcium and potassium). - Regulation of Vitamin D. - Renoprotective properties.
26 Renoprotective effects of Klotho: - Inhibition of cell senescence. - Inhibition of cell apoptosis. - Antioxidation. - Inhibition of fibrosis. - Activation of kidney regeneration. - Preservation of stem cells. - Protection of endothelial function. - Restoration of renal angiogenesis. Hu et al. Nat Rev Nephrol 2012
27 CKD is a state of Klotho deficiency Hu et al. Annu Rev Physiol 2013
28 Klotho beyond the kidney Cardiovascular dysfunction Klotho deficiency Donate-Correa et al. Cytokine Growth Factor Rev 2012
29 Klotho expression Parathyroid gland
30 Parathyroid gland in CKD Klotho expression Klotho Secondary hyperparathyroidism
31
32 Hu et al. JASN 2011
33 What about the expression of the Klotho gene in the human vascular wall?
34 Donate-Correa et al. Int J Cardiol 2011
35 Lim et al. Circulation 2012
36 Lim et al. Circulation 2012
37 Flow mediated dilatation Pulse wave velocity Intima-media thickness Aortic calcification index Kitagawa et al. PlosOne 2013
38 CKD is a state of Klotho deficiency Moreno et al. JASN 2011
39 Young & Wu. KI 2012
40 Is there any relationship between Klotho and atherosclerotic disease?
41 Atherosclerosis: an inflammatory disease
42 Klotho gene polymorphism and ischemic heart disease KL-VS polymorphism G-395A polymorphism p=0.03 % A -395G Choi et al. Int Heart J 2009 Arling et al. Am J Human Genet 2003
43 % of subjects with Cardiovascular Disease * Tertil of plasma klotho * p<0.001 CVD: coronary heart disease, heart failure, stroke, peripheral vascular disease Semba et al. J Am Geriatr Soc 2011
44 Klotho and Coronary Artery Disease 468 patients 371 patients underwent coronary angiography Serum samples 97 patients under elective cardiac surgery Thoracic aorta samples Navarro-González et al. Heart 2014
45 Serum Klotho and coronary heart disease pg/ml p<0.001 No (N=139) Yes (N=232) Navarro-González et al. Heart 2014
46 Klotho expression and coronary heart disease mrna (u.a.) p<0.01 No (N=27) Yes (N=50) Navarro-González et al. Heart 2014
47 Serum Klotho and coronary heart disease LOGISTIC REGRESSION Dependent variable: Presence / Absence significant CAD MODEL - Age, sex tobacco, Hypertension, diabetes, dyslipidemia BP, BMI, Uric acid, Ca, P, CRP, FGF23, Klotho OR IC 95% P Age <0.05 Hypertension <0.05 Diabetes <0.05 Tobacco <0.01 CRP <0.001 Klotho <0.001 Navarro-González et al. Heart 2014
48 Energy metabolism Anti-inflammatory Antioxidation Antiaging Antiapoptosis Wnt signal transduction Glucose metabolism Anti-renin-angiotensin system
49
50 Inflammation Atherosclerosis Manolis A. Hosp Chron 2012
51 Hu et al. Annu Rev Physiol 2013
52 Hu et al. Annu Rev Physiol 2013
53 Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning Sir Winston Churchill
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