Le Malattie Rare : un Utile Modello Fisiopatologico Prof. Giovambattista Capasso Cattedra di...
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Transcript of Le Malattie Rare : un Utile Modello Fisiopatologico Prof. Giovambattista Capasso Cattedra di...
Le Malattie Rare : un Utile Modello Fisiopatologico
Prof. Giovambattista Capasso
Cattedra di Nefrologia
Seconda Università di Napoli
MALATTIE RAREMALATTIE RARE
Ad oggi si conoscono circa 8000 malattie rare,
che nel complesso interessano 30 milioni di
persone in Europa e circa 0.5 milione in Italia
Malattie rare = Malattie ‘orfane’
Perche studiare la malattie rare?
Motivi etici Il bene più grande della società è la SALUTE della popolazione e quello alla salute è un diritto universale
Motivi socio-economiciMigliorare la conoscenza delle malattie rare si traduce in vantaggi per lo stato di salute e la qualità della vita
Motivi scientificiLo studio di patologie rare rappresenta uno strumento utile alla comprensione di processi di fisiologia e patologia
Aim of this lecture To show whether rare diseases have been used as
models to delineate specific aspects of renal physiology and pathology
Lesson to be learnedThe study of rare disease may lead to an understanding of
common disorders
BASIS OF HYPERTENSIONBASIS OF HYPERTENSION
Essential hypertension.: contribution of enviromental factors (obesity, smoke,atherosclerosis, hormones,etc.) and predisposing inheritable factors
Serie1; 90%
Serie1; 10%
1 2
ESSENTIAL HYPERTENSION: 90%
SECONDARY HYPERTENSION: 10%
Secondary hypertension: known pathophysiological factors, among which genetic inheritable mutations
Normal Na+ handling in renal tubules
PT
TAL
CNT
CD
Na+Na+
Na+
Na+
25% OF Na+ REABSORBED
DCT5% OF Na+ REABSORBED
-
2-5%OF Na+
REABSORBED
60% OF Na+ REABSORBED
Na+ handling mediated by ENaC in ASDN cells(DCT2-CNT-CD)
Na+ K+Em=-65mV
Na+
LUMEN
INTERSTITIUM
Na+
Na+
Na+
K+ K+
K+K+
ATP-ase
ROMKENaC ENaC
DCTTAL
PT
DCT
CNT
CD
Na+
Na+
H+-ATP ase
H+
H+
H+
- - -- -INCREASED LUMEN ELECTRONEGATIVITY
Na+ 1.0 %10 d
Aldosteron~30 ng/dl
Na+ 0.01%10 d
Aldosteron~160 ng/dl
Subcellular Localization of ENaC Changes with Dietary Na+ Intake
Loffing et al. AJP 279: F252 (2000)
Liddle’s Syndrome: clinical features:
• Autosomal dominant inheritance with high penetrance
• Early onset: mostly in childhood but also in youth (10-30 years)
• Clinical signs typical of primary hyperaldosteronism:hypertension resistant to common therapies, metabolic alkalosis, hypokalemia, normal renal function, suppressedPRA and low/untreaceble plasmatic aldosterone.
•Severe cardiovascular sequelae when left untreated
• Normalization of BP with ENaC blocking agents (amiloride,triamterene) and low sodium diet.
Heterogeneous Syndrome
Liddle’s Syndrome: clinical features
Hypokalemia
Hypertension
Liddle’s Syndrome
PY m
ut
PY m
ut
PY m
ut
PY m
ut
UBIQUIT. UBIQUIT.UBIQUIT.UBIQUIT.
PROTEOSOME
-PROTEOSOMICDEGRADATION
Na+
Na+
Na+Na+
Na+
Na+
Na+
Na+
Na+
Na+
Na+Na+
Increased Po
Connecting tubule profile from wild type and Liddle mice
Pradervand J Am Soc Nephrolo 2003
Hypertension resistant to conventional therapy
Hypokalemia Hyperactivation of
ENaC due to hormonal stimuli (insulin, aldosteron)
Hypertension resistant to conventional therapy
Hypokalemia Hypercativation of ENaC
due to genetic mutaion
Analogies between LS and Obesity-related hypertension
Liddle syndrome Obesity-related hypertension
DT cell
TAL cell
Cl-
Na+
3Na+
2K+
K+
K+
Na+
2Cl
recycling
Na absorption along the TAL and DT
Cl-
TAL
3Na+
2K+DT
Cl-
Tubular localization of the molecular defects
BartterBartter
GitelmanGitelman
TAL
DCT
Lumen Blood
Transport proteins involved in the pathogenesis of Bartter syndrome
NaNa++
2Cl2Cl--
KK++
3 Na3 Na++
2 K2 K++ATP
ClCl-- KK++
Type 1Type 1 XNKCCNKCC
XType 2Type 2
CaCa2+2+
MgMg2+2+
ROMKROMKClCKa/bClCKa/b
BartinBartin
X Type 3Type 3
X Type 4Type 4
CaSRCaSRX Type 5Type 5
Lumen Blood
Na+
Cl-
3 Na+
2 K+ATP
Cl-
Ca+2
X
Molecular defects in Gitelman syndrome
Ca+2
ATPATP
Polyhydramnios Prematurity Metabolic alkalosis Hypokalemia Dehydration Polyuria Polydipsia Hypercalciuria/
nephrocalcinosi Orthostatic hypotension
Hypokalemia Metabolic alkalosis Hypomagnesemia with
urinary magnesium wasting
Low urinary calcium excretion
Childhood Orthostatic hypotension
Gitelman’s syndromeBartter’s syndrome
Familiar Hyperkaliemia and Hypertension (FHH) (Pseudohypoaldosteronism type II or Gordon Syndrome)
FHH is an autosomal dominant disordercharacterized by:
Hyperkalemia with hypertensionNormal GFRLow reninHypercalciuriaHigh response to thiazide diuretics
Severe FHH clinical features are :
Muscular weakness Hyperchloremic metabolic acidosis Short stature Intelligence below average
History of FHH
1964 - Paver & Pauline described the first case of 15-year-old Australian boy affected by hyperkalemia with hypertension and normal renal function
1969 - Arnold & Healy restudied the same patient; they measured plasma renin and aldosterone that were found to be low
1970 - Gordon et al. reported the case of 10-year-old Australian girl who presented with short stature, hypertension and hyperkalemia. Plasma renin activity was undetectable, aldosterone secretion was low-normal
1973 - de Wardener included Gordon’s syndrome with Liddle’s and Bartter’s syndrome in the disorders resulting from congenital defects of tubular function
2001 - Wilson et al. demonstrated the mutations in WNK kinases
Two syndromes with ‘mirror’ features
HypokalemiaMetabolic AlcalosisHypocalciuriaHypereninemiaHypotension/Normal
blood pressure
HyperkalemiaMetabolic AcidosisHypercalciuriaHyporeninemiaHypertension
Gitelman syndrome Gordon syndrome
Effects of WNK4 on NCCT expression in Xenopus oocytes
Wilson FH et al. PNAS 2003Wilson FH et al. PNAS 2003
Uninjected NCCT WNK4 + NCCT
Effects of WNK1 and WNK4 on NCC mediated 22Na uptake in Xenopus oocytes
HH22OO WNK1WNK1NCCNCC NCC +NCC +WNK1WNK1
00
11
22
33
44
22
22 N
aN
a Up
take (
% o
f N
CC
T a
lon
e)
Up
take (
% o
f N
CC
T a
lon
e)
55
66
WNK4WNK4 NCC +NCC +WNK4WNK4
NCC +NCC +WNK1+WNK1+WNK4WNK4Yang et al. - J Clin Invest 2003Yang et al. - J Clin Invest 2003
cRNAcRNA
cRNA + cRNA + HCTZHCTZ
NCCT NCCTWNK4
(Kinase - Dead)
NCCTWNK4(WT)
NCCTWNK4
(Q562E)
P< 1x10-9
NS
NS
Effects of WNK4 NCCT mediated 22Na flux in Xenopus oocytes
Wilson FH et alWilson FH et alPNAS 2003PNAS 2003
0
20
40
60
80
100
120
140
22 N
a Up
take (
% o
f N
CC
T a
lon
e)
WNK : a “molecular switch” that controls renal excretion of Na+ and
K+
BaselineNormal Aldosterone
HyperkaliemiaHigh Aldosterone
HypovolemiaHigh Aldosterone
WNK4WNK4
Blo
od
Blo
od
Lum
en
Lum
en
Cl-
Na+
Cl- Cl-
Na+Na+
K+
K+
K+K+
K+K+
WNK4WNK4
Cl- Cl-
Na+Na+
K+
K+
K+
CONCLUSIONI
• Lo studio delle malattie rare è utile alla comprensione di aspetti di fisiologia e fisiopatologia
• L’osservazione clinica di patologie rare ha contribuito alla caratterizzazione della funzione renale nell’equilibrio idro-elettrolitico e nel controllo della BP
• I Meccanismi fisiopatologici alla base di malattie rare spesso sono condivisi da disordini comuni, pertanto la loro conoscenza può fornire il razionale per lo sviluppo di strategie terapeutiche per altre patologie