Vylučování kyseliny močové

GIT

• 20–25 % eliminována gastrointestinálním traktem
• Může být dále degradována bakteriemi na
• NH3
• CO2 [4]
• Drug research for inhibiting intestinal excretion has been rare [10]
• ABCG2 in intestinal handing of urate
• ABCG2 knockout mice
• Reduced intestinal urate excretion
• Higher serum urate levels
• Lacking ABCG2 in the kidneys
• Renal urate excretion in this situation is still higher than normal
• Other transporters in the kidney can partially compensate [13]

• Metabolized by gut bacteria in a process termed intestinal uricolysis [26]

1-NPT1

1-NPT4

Ledvinami

• 75–80 % ledviny [4]

1. Glomerulární filtrace

• Volně filtrována glomerulem ( minimálně vázána na bílkoviny)
• Do primární moči

2. reabsobce v proximálním tubulu

• Většina k. močové

From renal tubular cavity to renal tubular epithelial cells

• Mainly by URAT1

Across the tubular epithelial basement membrane Into blood

• Mainly by GLUT9

3. Sekrece v distální části proximálního tubulu

Tubulární sekrece kyseliny močové

• Může být inhibována
• Při současné zvýšené exkreci jiných organických kyselin
• Kyselina acetoctová
• Beta-hydroxymáselná
• Mléčná
• Některé léky

4. Postsekreční reabsorpce

• Occurs at the S3 segment of the proximal tubule (80% of the excreted urate)
• Approximately 10% of the filtered uric acid appears to be excreted in the urine [26]
• 2% left as a percentage filtered to be excreted in the final urine [26]

Zvýšená sekrece k. močové ledvinami

• Rizikový faktor
• Pro vývodné močové cesty
• Pro ledvinný parenchym
• Urátová urolitiáza
• Zvýšené riziko jedinci s trvale kyselejší a koncentrovanější močí

9-MCT9

PDZK1 „URAT1-PDZ-NPT1”

hUAT1

Galectine-9

ABCG2 gene encodes a uric acid efflux transporter

• Proximal renal tubule
• Apical brush border membrane in polarized renal epithelial cells
• Secretory urate transporter in the proximal tubule
• Mutations in the ABCG2 gene - loss-of-function mutations
• Increase serum urate concentrations
• ABCG2 is a high-capacity, low-affinity exporter of uric acid [18]
• 2 cholesterol molecules bound in the multidrug-binding pocket located in
• A central, hydrophobic, inward-facing translocation pathway
• Between the transmembrane domains

Glucose transporter 9 (GLUT9/SLC2A9)

• Play important roles in uric acid reabsorption [10]
• Li et al. first reported that GLUT9 (SLC2A9) is a gene correlated with SUA level
• Similar results have been reported by several other studies
• Human GLUT9 has two isoforms depending on the splicing of the intracellular part of the N-terminal region
• GLUT9N
• Short form expressed at the apical side
• Transports uric acid from renal tubular cavity into epithelial cells
• GLUT9
• Long form expressed at the basal side
• Transits uric acid from epithelial cells into tubulointerstitium or blood
• More important role than URAT1 in the absorption of uric acid [10]

Glucose transporter 9 (GLUT9/SLC2A9) - URAT1v

• Play important roles in uric acid reabsorption [10]
• Li et al. first reported that GLUT9 (SLC2A9) is a gene correlated with SUA level
• Similar results have been reported by several other studies
• Basolateral entry of urate into the renal proximal tubule cells
• Voltage-dependent urate transport (URAT1v) known as GLUT9
• SLC2A9 gene on chromosome 4
• Reported initially as a hexose transporter (glucose and fructose) [26]
• Considered the principal regulators of uric acid in humans
• Human GLUT9 has two isoforms depending on the splicing of the intracellular part of the N-terminal region
• GLUT9N - GLUT9S
• Short form expressed at the apical side
• Transports uric acid from renal tubular cavity into epithelial cells [10]
• GLUT9 - GLUT9L
• Long form expressed at the basal side
• Transits uric acid from epithelial cells into tubulointerstitium or blood
• More important role than URAT1 in the absorption of uric acid [10]

OAT1 (SLC22A6) and OAT3 (SLC22A8)

• Urate/dicarboxylate exchangers
• Found on the basolateral side of the same cells that express OAT4
• Gene knockout studies in vivo
• Absence of OAT1 or OAT3
• Slightly decreased uricosuria
• Suggesting that their principal function is in urate excretion [10]

Human organic anion transporter (hOAT1) - stimulation / up-regulation

• Stimulates uric acid secretion in human proximal tubules [10]
• In the basolateral (OAT 1 and 3) [26]

Inhibited by

• Antiuricosuric drugs [8]
• Commonly used uricosuric drugs too :-( [8]

OAT 2

• OAT family - SLC22 genes
• Apical (OAT 2 and 4) membrane of the renal proximal tubules [26]

OAT3 (SLC22A8)

• uric acid secretion in human proximal tubules [10]
• In the basolateral (OAT 1 and 3) [26]

Human organic anion transporter 4 (hOAT4)

• Role in urate re-absorption in proximal tubules
• Dietary treatment of hyperuricemia
• Increased urine pH facilitate uric acid excretion [17]

Sodium-coupled transporters (gene SLC5A8)

• Favor renal reabsorption of uric acid
• Cotransporter
• Independent and sinergical pathway in URAT1 for carboxylic acids
• Lactate
• Butyrate
• Nicotinate
• Beta-hydroxibutyrate
• Acetoacetate [26]

Urate/anion exchanger (URAT1)

Urate anion exchanger 1 (URAT1/SLC22A12)

• Kidney specific urate transporter URAT1
• SLC22A12 gene on the chromosome 11q13
• A member of the OAT branch
• Apical brush border membrane of the renal proximal tubule
• Apical (luminal) uptake of urate from the primary urine to the proximal tubule cell
• Thus affecting reabsorption
• Favours urate ion exchange by anions
• Through the tubule for maintaining electrical balance
• First identified by Enomoto et al.
• Drug target that alters serum uric acid levels
• Causes idiopathic renal hypouricemia

Inhibice

• Some uricosuric drugs:
• Probenecid
• Indomethacin (analgetikum)
• 6-hydroxybenzbromarone
• Salicylate [10]
• Angiotensin II receptor blocker, losartan [8]

Urate transporter (UAT)

• Facilitate urate efflux out of the cells [8]