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Pre-eclampsia:A Pregnancy-Induced Autoimmune Disease?
Nephrology Journal ClubOctober 28, 2008
Pre-eclampsia
• Definition:– New onset of hypertension and proteinuria after 20 weeks of
gestation in a previously normotensive woman– In the setting of chronic hypertension
• New onset proteinuria • A sudden increase in blood pressure • Thrombocytopenia • Elevated LFTs
• Diagnostic Criteria:– Hypertension
• Systolic Blood Pressure ≥ 140mmHg, OR• Diastolic Blood Pressure ≥ 90mmHg
– Proteinuria (≥ 0.3g / 24hr)• 3 – 5% of pregnancies (US)
Severe preeclampsia:Clinical findings
• Systemic endothelial dysfunction / microangiopathy• IUGR (small for gestational age fetuses)
• Target organ dysfunction– Brain Seizures– Liver HELLP– Kidney Glomerular endotheliosis and proteinuria
Stillman and Karumanchi. JASN 2007. 18:2281.
Preeclampsia:Pathophysiology
• Placenta
• Predisposing risk factors:– Family history of preeclampsia (4-fold increased risk)– Nulliparity (or prolonged inter-pregnancy interval)– Multiple gestation– Molar pregnancies– Older maternal age– Preexisting hypertension– Chronic kidney disease– DM (and increased insulin resistance)– Black race– Thrombotic vascular disease
• Hypoperfusion and ischemia (Page. Am J Obst Gyn 1939. 37:291.)
Effects of chronic RUPP on MAP
Alexander et al. HTN 2000. 37:1191.
Effects of RUPP on renal hemodynamics
Alexander et al. HTN 2000. 37:1191.
Pre-eclampsia:Pathophysiology
Redman and Sargent. Science 2005. 308:1592.
Pre-eclampsia:Pathophysiology
Redman and Sargent. Science 2005. 308:1592.
VEGF• VEGF
– Promoter of angiogenesis– Induces nitric oxide– Induces vasodilatory
prostacyclins in endothelial cells– Glomerular healing
• anti-VEGF– Increase apoptosis– Impair glomerular capillary repair– Increase proteinuria (rat MPGN
model)• Exogenous VEGF
– ↓ CyA-mediated HTN, endothelial dysfunction, and nephropathy
• VEGF signaling inhibitors– HTN– Proteinuria
Eremina et al. Neph Physiol 2007. 106:32.Redman and Sargent. Science 2005. 308:1592.
Soluble fms-like tyrosine kinase 1 (sFlt1)
• Soluble receptor for VEGF
• Produced by the placenta
• VEGF and PlGF antagonist
• Increased in preeclampsia– Placental sFlt1
expression– Amniotic fluid levels
Davison et al., JASN 2004. 15:2440.Redman and Sargent. Science 2005. 308:1592.
Excess placental sFlt1 may contribute to preeclampsiaMaynard et al. JCI 2003. 111(5):649.
1 2
Impaired angiogenesis due to ↑sFlt1 in preeclampsia
Maynard et al. JCI 2003. 111(5):649.
sFlt1 inhibits VEGF- and PlGF-induced vasodilation of renal microvessels
Maynard et al. JCI 2003. 111(5):649.
sFlt1 response and PlGF expression
pregnantnonpregnant
+ control
Maynard et al. JCI 2003. 111(5):649.
sFlt1 induces glomerular endotheliosis
Maynard et al. JCI 2003. 111(5):649.
Angiotensin II Induces sFlt1 release in pregnancyZhou et al. Circ Res 2007. 100:88.
• Angiotensin II– Potent vasoconstrictor– ↑ with sFlt1 in pregnancy– May promote sFlt1
expression in pregnancy
1
2 - Human Placental Explants
Ang II induces the synthesis and secretion of sFlt1 by human trophoblasts via AT1 receptor activation
Calcineurin signaling functions downstream of the AT1R to mediate Ang II-induced sFlt1 production
Patients with preeclampsia develop agonistic autoantibodies against the AT1 receptor
Wallukat et al. JCI 1999. 103:945.
• Preclamptic pts have an exaggerated pressor response to Ang II
• Circulating Ang II levels are not increased in preeclampsia
• Model beating neonatal rat cardiomyocytes
1
2a
2b
Effects of IgG from preeclamptic patients
1 2
3 4
Wallukat et al. JCI 1999. 103:945.
VSMCs exposed to IgG from preeclamptic patients
Wallukat et al. JCI 1999. 103:945.
Effect of PKC inhibition
SUMMARY• IgG from preeclamptic
patients contains agonistic antibodies that binds the AT1R (second loop)
• Antibody subsides after delivery
• An AT1R antibody was found on VSMCs
• Post-receptor signaling involves PKC
Wallukat et al. JCI 1999. 103:945.
AT1-AAs interact with specific sequences on second EC-loop of AT1 receptor
Effects of AT1-AAs from preeclamptic patients
• AT1-AAs activate AT1R on human mesangial cells and induce IL-6 and PAI-1 secretion– Bobst et al. AJH 2005. 18:330.
• AT1-AAs cause vascular cells to express tissue factor– Dechend et al. Circulation 2000. 101:2382.
• AT1-AAs (through ↑ NADPH oxidase expression) contribute to reactive oxygen species production that may upregulate NF-kB– Dechend et al. Circulation 2003. 107:1632.
• AT1-AAs account for ↑ intracellular Ca2+ mobilization– Thway et al. Circulation 2004. 110:1612.
Angiotensin receptor agonistic autoantibodiesinduce pre-eclampsia in pregnant mice
Zhou et al. Nat Med 2008. 14(8):855-862.
Methods:Fig 1a-c. Injection of hIgG in pregnant mice
MS = Mouse serum without injectionNT = Normotensive PE = Pre-eclampticHC = IgG Heavy chain LC = IgG Light chain
Zhou et al. Nat Med 2008. 14(8):855-862.
Results:Fig 1d-e. BP and proteinuric effects of hIgG injection
Zhou et al. Nat Med 2008. 14(8):855-862.
Results:Fig 2a-d. Affinity-purified AT1-AAs
Zhou et al. Nat Med 2008. 14(8):855-862.
Results:Fig 2e-f. Affinity-purified AT1-AAs
Zhou et al. Nat Med 2008. 14(8):855-862.
Results:Fig 3a-c. Renal Pathology – LM
Zhou et al. Nat Med 2008. 14(8):855-862.
Results:Fig 3d. Renal Pathology – EM
Zhou et al. Nat Med 2008. 14(8):855-862.
Results:Table S1 / Fig S1a-b. Placental and fetal weight
Zhou et al. Nat Med 2008. 14(8):855-862.
Results:Fig S2. AT1-AAs induce sFlt1 and sEng production
Zhou et al. Nat Med 2008. 14(8):855-862.
Results:Fig 4a-b. hIgG effects in nonpregnant mice
Zhou et al. Nat Med 2008. 14(8):855-862.
Results:AT1-AA – mediated HTN does not require sFlt1
1d 4b2e
Pregnant mice Non-pregnant mice
Zhou et al. Nat Med 2008. 14(8):855-862.
Results:Fig 4c-d. hIgG effects in nonpregnant mice
Zhou et al. Nat Med 2008. 14(8):855-862.
Results:AT1-AA – mediated proteinuria requires sFlt1
1e 4c2f
Pregnant mice
Non-pregnant mice
Zhou et al. Nat Med 2008. 14(8):855-862.
Results:AT1-AA – mediated glomerular endotheliosis requires sFlt1
4c
3b
Non-pregnant mice
Pregnant mice
Zhou et al. Nat Med 2008. 14(8):855-862.
Conclusions
• AT1-AAs (via AT1R activation) cause:– Elevated BP (± sFlt1)– Heavy proteinuria
(+sFlt1)– Glomerular
endotheliosis (+sFlt1)
• Placental ischemia may serve as a key stimulus for AT1-AA production during pregnancy
• AT1-AAs = potential therapeutic target
Zhou et al. Nat Med 2008. 14(8):855-862.
Parikh, Karumanchi. Nat Med 2008. 14(8):810-812.
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