Mecanismo de transporte tubular

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Seminario de Fisiología Renal MECANISMOS DE TRANSPORTE TUBULAR
Dr. Ernesto Castro Aguilar
Julio 2014
TRANSPORTE EPITELIAL
Filtrado glomerular sufre una serie de modificaciones antes de
convertirse en orina
Reabsorción y secreción de solutos y fluidos
TRANSPORTE
EPITELIAL
TRANSPORTE TUBULAR
Propiedades de membrana luminal deben ser diferentes a
membrana basolateral. Distribución asimétrica de proteínas transportadoras.
Transporte transcelular y paracelular (limitado por uniones
estrechas)
TRANSPORTE PASIVO
Difusión simple: gradiente electroquímico. No requiere energía
Difusión facilitada: interacción de molécula o ión con
transportador de membrana que favorece paso por membrana
bilipídica.
Difusión por canal: favorece paso a una tasa mayor.
REABSORCIÓN
Movimiento de solutos o agua desde lúmen tubular hacia la
sangre
Importante para manejo de Na+, Cl-, H2O, bicarbonato, glucosa,
aminoácidos , proteínas, fosfatos, Ca2+, Mg2+, urea, ácido úrico y
otras moléculas
SECRECIÓN
Movimiento de solutos desde la sangre o intersticio celular hacia
el lúmen tubular.
Manejo de H+, K+, amonio (NH4+) y ácidos y bases orgánicas.
TRANSPORTE ACTIVO
Energía es requerida para transportar iones contra gradiente
electroquímico.
Energía derivada de metabolismo celular
Mecanismo más importante es el de la bomba Na-K.
Confinada a membrana basolateral.
Energía de hidrólisis de ATP.
NA+-K+-ATPASA
Clave para el funcionamiento de mecanismos de transporte
pasivo.
Mantiene concentración intracelular de sodio (10-20 mmol/L) y
de potasio (150mmol/L)
Necesario para funcionamiento de cotransportadores,
antiportadores.
TÚBULO PROXIMAL
Adaptado para reabsorción en “masa”.
Células con borde en cepillo en superficie apical Membrana basolateral con pliegues que también aumentan
superficie.
Ricas en mitocondrias y vacuolas lisosomales
Pocas uniones intercelulares
Major Transport Mechanisms Along the Nephron
DCT
Lumen
Principal cells
Interstitium
Lumen
Na+
Na+
Cl−
K+
Na+
Na+
K+
K+
K+
K+
Cl−
Ca2+
Interstitium
Ca2+
!
Ca2+
Na+
Intercalated cells
PCT
Lumen
Na+
Glucose
Na+
Amino acids
Na+
Phosphate
Na+
Citrate
Cl−
Formate/Oxalate
Na+
H+
Alpha
Interstitium
Glucose
Amino acids
Na+
K+
K+
Cl−
K+
Cl−
Na+
HCO3−
H+
HCO3−
Cl−
H+
K+
Cl−
Beta
H+
HCO3−
Cl−
Cl−
TUBULO PROXIMAL
Responsable de reabsorción de Na+, K+, Cl- y HCO3-. Reabsorción prácticamente completa de glucosa, aminoácidos y
proteínas de bajo peso molecular (b-microglobulinas, proteína
ligadora de retinol). Reabsorción 60% calcio, 80% fosfato y 50% urea
TÚBULO PROXIMAL
Altamente permeable a agua (no hay generación de gradiente
osmótico)
S2 y S3: secreción de ácidos y bases orgánicas débiles (diuréticos
y PAH).
ASA DE HENLE
Conformada por:
Pars recta de TP (asa descendente gruesa)
Asas delgadas descendente y ascedente (presente en nefronas con asas
largas) Asa gruesa ascendente
Mácula densa
Responsable de reabsorción mayor de Mg2+ y concentración o dilución de
orina.
limbs of deep nephrons). (Recent evidence suggests that the thin
Transport Mechanisms in
the Thick Ascending Limb
Lumen
Cells of thick ascending limb
Interstitial fluid
Na+
K+
Na+
H+
Na+
K+
Ca2+
Mg2+ +
K+
K+
2Cl−
Na+
K+
K+
Cl−
Cl−
Paracellular
diffusion
Lumen-positive
potential difference
Figure 2.12 Transport mechanisms in the thick ascending limb of
Henle. The major cellular entry mechanism is the Na+-K+-2Cl− cotransporter. The transepithelial potential difference drives paracellular trans-
again driven b
low intracellul
lumen throug
to a much less
apical NKCC
of action of lo
exits the cell
through basol
also re-enters
potassium cha
necessary for n
presumably be
the transporte
lower than tha
sible for gener
in this segmen
reabsorption
reabsorbed tra
larly (see Fig.
reabsorbed by
TAL in the ab
the tubular fl
name diluting
The U-sha
Henle, the di
ascending lim
in the TAL ar
TÚBULO DISTAL
Conformado por: túbulo contorneado distal, túbulo conector y
ducto colector
Conducto colector cortical: 2 células
Principales : reabsorción de Na+ y secreción de K+.
ENaC: genera gradiente eléctrico
Intercaladas: secreción de H+ (alfa) o bicarbonato (beta)
TÚBULO DISTAL
Ducto colector medular Pérdida de células intercaladas
Modificación de células principales: no secretan K+ en esta
porción.
Major Transport Mechanisms Along the Nephron
DCT
Lumen
Principal cells
Interstitium
Lumen
Na+
Na+
Cl−
K+
Na+
Na+
K+
K+
K+
K+
Cl−
Ca2+
Interstitium
Ca2+
!
Ca2+
Na+
Intercalated cells
PCT
Lumen
Na+
Glucose
Na+
Amino acids
Na+
Phosphate
Na+
Citrate
Cl−
Formate/Oxalate
Na+
H+
Alpha
Interstitium
Glucose
Amino acids
Na+
K+
K+
Cl−
K+
Cl−
Na+
HCO3−
H+
HCO3−
Cl−
H+
K+
Cl−
Beta
H+
HCO3−
Cl−
Cl−
CHAPT
Renal Sodium Handling
Distal convoluted tubule
8%
Cortex
5%
Proximal
convoluted
tubule
50%
Proximal
straight
tubule 15%
Outer
medulla
3%
Collecting duct
Connecting
tubule
35%
20%
Thick
ascending
limb
7%
Inner
medulla
Thin
descending
limb
Thin
ascending
limb
!1%
Figure 2
the neph
resent th
tered load
within the
remaining
the proxim
day-to-day
in the dist
Renal Potassium Handling
Distal convoluted tubule
10%
Cortex
Proximal
convoluted
tubule
45%
Proximal
straight
tubule
Outer
medulla
Inner
medulla
Connecting
tubule
Thick
ascending
limb
Thin
descending
limb
Thin
ascending
limb
1%–100%
Collecting duct
Figure
the nep
ages rea
because
but mos
proximal
limb of H
load reac
connecti
late dist
able and
excretion
Defects in Transport Proteins Resulting
in Renal Disease
Transporter
Consequence of Mutation
Peritubular Capi
Fluid Rea
Lumen
Nor
Proximal tubule
Proximal Tubule
Apical Na+-cystine cotransporter
Cystinuria
Apical Na+-glucose cotransporter
(SGLT2)
Renal glycosuria
Proximal renal tubular
acidosis
Basolateral Na+-HCO3– cotransporter
Na+
+
H2O Na+ K
Paracellular
backflux
Intracellular H+-Cl– exchanger (CIC5) Dent disease
Thick Ascending Limb
Apical Na+-K+-2Cl– cotransporter
Bartter syndrome type 1
Apical K+ channel
Bartter syndrome type 2
Cl– channel
Bartter syndrome type 3
Basolateral Cl– channel accessory
protein
Bartter syndrome type 4
Basolateral
Distal Convoluted Tubule
Apical
Na+-Cl–
cotransporter
Gitelman’s syndrome
Reduced peritubular ca
Na+
+
H2O Na+ K
Increased
paracellular
backflux
Collecting Duct
Apical Na+ channel (principal cells)
Overexpression: Liddle’s
syndrome
Underexpression:
pseudohypoaldosteronism
type 1b
Aquaporin-2 channel
(principal cells)
Nephrogenic diabetes
insipidus
Basolateral Cl–/HCO3– exchanger
(intercalated cells)
Distal renal tubular acidosis
Apical H+-ATPase (intercalated cells) Distal renal tubular acidosis
(with or without deafness)
Figure 2.10 Genetic defects in transport proteins resulting in
renal disease. For more detailed coverage of these clinical conditions,
Figure 2.11 Physical factors an
Influence of peritubular capillary onc
proximal tubules. Uptake of reabs
determined by the balance of hydro
the capillary wall. Compared with th
tubular capillary hydrostatic (Ppc) and
high, respectively, so that uptake of
capillaries is favored. If peritubular
(or hydrostatic pressure increases),
sure increases, and more fluid may
larly; net reabsorption in proximal tu
Major Transport Mechanisms Along the Nephron
DCT
Lumen
Principal cells
Interstitium
Lumen
Na+
Na+
Cl−
K+
Na+
Na+
K+
K+
K+
K+
Cl−
Ca2+
Interstitium
Ca2+
!
Ca2+
Na+
Intercalated cells
PCT
Lumen
Na+
Glucose
Na+
Amino acids
Na+
Phosphate
Na+
Citrate
Cl−
Formate/Oxalate
Na+
H+
Alpha
Interstitium
Glucose
Amino acids
Na+
K+
K+
Cl−
K+
Cl−
Na+
HCO3−
H+
HCO3−
Cl−
H+
K+
Cl−
Beta
H+
HCO3−
Cl−
Cl−
Renal Anatomy and Physiology
Proteins Resulting
Disease
Consequence of Mutation
Peritubular Capillaries Modulate
Fluid Reabsorption
Lumen
Cystinuria
Na+
+
H2O Na+ K
Renal glycosuria
Proximal renal tubular
r
acidosis
Normal
Proximal tubule Interstitial
fluid
Peritubular
capillary
Ppc
(low)
Paracellular
backflux
πpc
(high)
5) Dent disease
Fluid
reabsorbed
Bartter syndrome type 1
Bartter syndrome type 2
Reduced peritubular capillary oncotic pressure
Bartter syndrome type 3
Bartter syndrome type 4
Gitelman’s syndrome
Overexpression: Liddle’s
syndrome
Underexpression:
pseudohypoaldosteronism
type 1b
Nephrogenic diabetes
insipidus
Na+
+
H2O Na+ K
Increased
paracellular
backflux
↓ πpc
Raised
interstitial
pressure
Less fluid
reabsorbed
Figure 2.11 Physical factors and proximal tubular reabsorption.
Influence of peritubular capillary oncotic pressure on net reabsorption in
proximal tubules. Uptake of reabsorbate into peritubular capillaries is
determined by the balance of hydrostatic and oncotic pressures across
FIN