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Biochemistry of the kidney mirka.rovenska@lfmotol.cuni.cz
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The main roles of the kidney Participation in amino acid / nitrogen metabolism Excretion of water, salts, and waste products (urea, uric acid…) Regulation of electrolyte and acid-base balance (homeostasis) Participation in biosyntheses (creatine, carnitine, glucose, AA) Participation in hormonal regulation
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AA/nitrogen metabolism during fasting During fasting, AA are released from skeletal muscle: Ala, Gln Sk. muscle oxidizes Val, Ile, Leu to produce energy and Gln The amino groups of Val, Ile, Leu, Asp, and Glu are transferred out of skeletal muscle in Ala and Gln Ala supplies gluconeo- genesis in the liver, Gln is taken up by the kidney and gut
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Branched-chain AA BCAA are the major AA that can be oxidized in tissues other than liver α- keto acids of the BCAA are either released into the blood and taken up by liver, or oxidized to CO 2, or con- verted to Gln
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Gln and Ala as nitrogen carriers Gln is generated mainly in the skeletal muscle from Leu, Ile, Val, and also by the lungs and brain from the removal of NH 4 + : Glu + ATP + NH 4 + Gln + H 2 O + ADP + P The kidney, the gut, and cells with rapid turnover rate (e.g. cells of the immune system) are the major sites of Gln uptake Here, Gln serves as a fuel and a nitrogen donor for syntheses; in the kidney, the glutaminase reaction is particularly important Much of the unused nitrogen from Gln is built into Ala which carries the nitrogen to the liver where it is converted to urea
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Ammonia release in the kidney 1) By glutaminase 2) By glutamate dehydrogenase α -ketoglutarate is used as a fuel by the kidney: oxidized to CO 2 or converted to glucose
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Glutamine as a fuel for the kidney The carbon skeleton of Gln forms α- ketoglutarate, which is oxidized to CO 2, converted to Glc, or released as S or A Glucose is used principally by the cells of the renal medulla Lactate is oxidized in renal cortical cells which have a higher mitochondrial capacity and a greater blood supply
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Ammonium is excreted into the urine
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Kidney in the regulation of the acid-base balance
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H + ion secretion In the proximal tubules, H + ions are secreted by secondary active transport with Na + : In the distal tubules and collecting duct, H + ions are secreted by H + -ATPase.
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Removal of H + ions from tubular fluid Reaction with ammonia Reaction with HCO 3 - Reaction with HPO 4 2- to form H 2 PO 4 -
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Proton removal by ammonia NH 3 diffuses through the membrane of the renal tubule cells into the urine Ammonia increases proton excretion by combining with a proton to form ammonium ion Shunting Gln from liver to kidneys also conserves bicarbonate (needed for urea formation)
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Glutaminase reaction in the regulation of acid-base balance In the kidney, NH 3 carried by Gln is excreted into the urine This process removes protons formed during fuel oxidation and helps to maintain the body‘s pH During metabolic acidosis: the kidney becomes the predominant site of Gln uptake the activities of renal glutaminase and Glu-dh increase the urinary excretion of NH 4 + increases severalfold the liver synthesizes less urea, making more Gln available for the kidney
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Reaction of H + with HCO 3 - Secreted H + ions promote HCO 3 - resorption: H + react with HCO 3 - in the primary urine to form H 2 O and CO 2, which diffuses back to the tubule cells and then into the blood
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Excretion by the kidney
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Urine formation 180 l of primary urine is filtered out of the 1500 l of blood flowing through the kidneys every day Primary urine is concentra- ted and 0,5-2 l of final urine is excreted per day Concentrating urine and transporting it through membranes require large amount of energy (ATP)
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Urine 95% water Organic components: urea uric acid creatinine AA and their derivatives (e.g. hippurate) metabolites of hormones xenobiotics pigments Inorganic ions (Na + and Cl - represent 2/3 of electrolytes)
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Creatinine excretion Creatine phosphate can readily regenerate ATP: Creatine phosphate is unstable and spontaneously cyclizes, forming creatinine, which is excreted in the urine
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Creatinine as an indicator The amount of creatinine excreted each day is constant and depends on body muscle mass It can be used as a gauge for urinary excretion of other compounds and as an indicator of renal excretory function Creatinine clearance (U Cr x V) / P Cr or estimates based on serum Cr are used to assess the glomerular filtration rate The amount of Cr can also be used to determine whether the sample truly represents a whole day‘s urinary output (140 – age). mass [kg] E.g.: C Cr = 48,9. serum Cr [µmol/l]
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Regulation of the electrolyte balance
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Electrolyte and water resorption CompoundResorption [%]Site of resorption Na + 99,4PT, HL, DT, CD K+K+ 93,3PT, HL, DT, CD Cl - 99,2PT, HL, DT, CD HCO 3 - 100PT, DT Urea53PT, HL, DT, CD Uric acid98PT Glucose100PT Water99,4PT, HL, DT, CD
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Calcium and phosphate ions: almost completely resorbed by active transport; resorption is regulated by: parathormone – produced by the parathyroid gland, Ca 2+ resorption, phosphate resorption calcitonin – produced by the thyroid gland, resorption of both Ca 2+ and phosphate calcitriol – formed in the kidney; resorption of both Ca 2+ and phosphate
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Sodium ions: More than 97% resorbed – by passive transport as well as secondary active transport Resorption is regulated by: aldosterone – Na + reuptake atrial natriuretic peptide (ANP) – Na + reuptake angiotensin II – increases resorption of Na + and HCO 3 - in the proximal tubule (see below) Water: passively resorbed (water follows the osmotically active particles, particularly Na + ) regulated by ADH in the collecting duct: ADH stimulates the transfer of aquaporins into the plasma membrane
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ADH (vasopressin) Nonapeptide released by the posterior pituitary in response to stimuli from baroreceptors and osmoreceptors, which sense a fall in blood pressure or a rise in extracellular Na + Stimulates aquaporin insertion in the luminal PM:
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Diabetes insipidus In the absence of ADH, the cells of the collecting duct are relatively impermeable for water and the diuresis increases Causes of diabetes insipidus: failure to produce ADH (e.g. due to damage of the pituitary gland or hypothalamus) inability of the kidney to response to ADH: mutation in the gene encoding for the receptor mutation in the gene encoding for aquaporin 2
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Biosyntheses in the kidney
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Gluconeogenesis in the kidney Under the more extreme condi- tions of starvation (2 days and more), renal gluconeogenesis also becomes significant Glc produced by the kidney cortex is used mainly by the kidney medulla, but some may enter the bloodstream to supply brain and RBCs The main substrate: AA (Gln) Regulated by cortisol
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Serine biosynthesis Serine biosynthesis: the major sites are the liver and kidney
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Conversion of Gly to oxalate Gly is degraded to glyoxylate which can be oxidized to oxalate Oxalate is sparingly soluble and tends to precipitate in kidney tubules, leading to formation of kidney stones
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Arg synthesis by the gut and the kidney The gut releases citrulline which is converted to Arg in the kidney Arg can be converted to creatine in the kidney or released into the blood The liver uses Arg to generate ornithine for the urea synthesis
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Creatine synthesis Creatine synthesis begins in the kidney and is completed in the liver Creatine travels through the bloodstream to other tissues, particularly skeletal muscle, heart, brain
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Carnitine synthesis Carnitine is derived from Lys residues which are N-methylated to form trimethyllysyl residues Trimethyllysine is released upon protein degradation Kidney and to a lesser extent liver carry out the complete pathway and supply other tissues, espe- cially muscle and heart
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Secretory function of the kidney Participation in the hormonal regulation
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The kidney secretes: renin 1,25-dihydroxycholecalciferol (vitamin D, calcitriol) erythropoietin
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Renin-angiotensin system Generates angiotensin II Renin – aspartic protease formed in the kidney; acts on angiotensinogen in blood ACE – found on the surface of endothelial cells, mainly pulmonary and renal
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The effects of AngII lead to increased blood pressure and sodium and water retention
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Aldosterone Producing cells: adrenal zona glomerulosa Functions: causes Na + reabsorption in the kidney, mainly in the distal tubule causes water retention raises blood pressure by increasing fluid volume
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Pharmacological intervention The renin-angiotensin system can be influenced by: angiotensin I analogs that inhibit ACE antagonists that block the binding of AngII to its receptors inhibitors of renin These drugs decrease blood pressure Captopril: ACE inhibitor
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Calcitriol 7-dehydrocholesterol is activated in the skin by sunlight to generate vitamin D 3 (cholecalciferol), which is hydroxylated: in the liver in position 25 then in the kidney in position 1 C-C bond cleavage opens the B-ring
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Hormone-receptor complex binds to response elements in DNA Result: increased rate of transcription of genes that encode a number of Ca 2+ -binding proteins (calbindins, Ca 2+ -ATPase…) stimulates the absorption of Ca 2+ and phosphate from the intestinal lumen also plays an important role in bone mineralization in the kidney, weakly stimulates Ca 2+ reabsorption
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Erythropoietin (EPO) Decreased supply of oxygen to the tissues signals the kidney to release erythropoietin In bone marrow, erythropoietin (glycoprotein) stimulates the multiplication and maturation of erythroid progenitors Reticulocyte: the nucleus is extruded, but ribosomes+mRNA are retained and enable the synthesis of Hb
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Renal eicosanoids PGE 2, PGI 2 dilate renal blood vessels and increase blood flow. PGE 2, PGD 2 increase water and salt excretion. 20-HETE regulates Na + excretion and diuresis 12- and 15-HETE influence the renin-angiotensin system (they probably mediate the feed-back inhibition of renin) PGE 2
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