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.