Pre-eclampsia: A Pregnancy-Induced Autoimmune Disease? Nephrology Journal Club October 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 :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 :291.)

Effects of chronic RUPP on MAP Alexander et al. HTN :1191.

Effects of RUPP on renal hemodynamics Alexander et al. HTN :1191.

Pre-eclampsia: Pathophysiology Redman and Sargent. Science :1592.

Pre-eclampsia: Pathophysiology Redman and Sargent. Science :1592.

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 :32. Redman and Sargent. Science :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 :2440. Redman and Sargent. Science :1592.

Excess placental sFlt1 may contribute to preeclampsia Maynard et al. JCI (5):

Impaired angiogenesis due to ↑sFlt1 in preeclampsia Maynard et al. JCI (5):649.

sFlt1 inhibits VEGF- and PlGF-induced vasodilation of renal microvessels Maynard et al. JCI (5):649.

sFlt1 response and PlGF expression pregnant nonpregnant + control Maynard et al. JCI (5):649.

sFlt1 induces glomerular endotheliosis Maynard et al. JCI (5):649.

Angiotensin II Induces sFlt1 release in pregnancy Zhou et al. Circ Res :88. Angiotensin II – Potent vasoconstrictor – ↑ with sFlt1 in pregnancy – May promote sFlt1 expression in pregnancy Human Placental Explants

Ang II induces the synthesis and secretion of sFlt1 by human trophoblasts via AT 1 receptor activation

Calcineurin signaling functions downstream of the AT 1 R to mediate Ang II-induced sFlt1 production

Patients with preeclampsia develop agonistic autoantibodies against the AT 1 receptor Wallukat et al. JCI :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 Wallukat et al. JCI :945.

VSMCs exposed to IgG from preeclamptic patients Wallukat et al. JCI :945.

Effect of PKC inhibition SUMMARY IgG from preeclamptic patients contains agonistic antibodies that binds the AT 1 R (second loop) Antibody subsides after delivery An AT 1 R antibody was found on VSMCs Post-receptor signaling involves PKC Wallukat et al. JCI :945.

AT 1 -AAs interact with specific sequences on second EC-loop of AT 1 receptor

Effects of AT 1 -AAs from preeclamptic patients AT 1 -AAs activate AT 1 R on human mesangial cells and induce IL-6 and PAI-1 secretion – Bobst et al. AJH :330. AT 1 -AAs cause vascular cells to express tissue factor – Dechend et al. Circulation :2382. AT 1 -AAs (through ↑ NADPH oxidase expression) contribute to reactive oxygen species production that may upregulate NF-  B – Dechend et al. Circulation :1632. AT 1 -AAs account for ↑ intracellular Ca 2+ mobilization – Thway et al. Circulation :1612.

Angiotensin receptor agonistic autoantibodies induce pre-eclampsia in pregnant mice Zhou et al. Nat Med (8):

Methods: Fig 1a-c. Injection of hIgG in pregnant mice MS = Mouse serum without injection NT = NormotensivePE = Pre-eclamptic HC = IgG Heavy chainLC = IgG Light chain Zhou et al. Nat Med (8):

Results: Fig 1d-e. BP and proteinuric effects of hIgG injection Zhou et al. Nat Med (8):

Results: Fig 2a-d. Affinity-purified AT 1 -AAs Zhou et al. Nat Med (8):

Results: Fig 2e-f. Affinity-purified AT 1 -AAs Zhou et al. Nat Med (8):

Results: Fig 3a-c. Renal Pathology – LM Zhou et al. Nat Med (8):

Results: Fig 3d. Renal Pathology – EM Zhou et al. Nat Med (8):

Results: Table S1 / Fig S1a-b. Placental and fetal weight Zhou et al. Nat Med (8):

Results: Fig S2. AT 1 -AAs induce sFlt1 and sEng production Zhou et al. Nat Med (8):

Results: Fig 4a-b. hIgG effects in nonpregnant mice Zhou et al. Nat Med (8):

Results: AT 1 -AA – mediated HTN does not require sFlt1 1d4b 2e Pregnant mice Non-pregnant mice Zhou et al. Nat Med (8):

Results: Fig 4c-d. hIgG effects in nonpregnant mice Zhou et al. Nat Med (8):

Results: AT 1 -AA – mediated proteinuria requires sFlt1 1e 4c2f Pregnant mice Non-pregnant mice Zhou et al. Nat Med (8):

Results: AT 1 -AA – mediated glomerular endotheliosis requires sFlt1 4c 3b Non-pregnant mice Pregnant mice Zhou et al. Nat Med (8):

Conclusions AT 1 -AAs (via AT 1 R activation) cause: – Elevated BP (± sFlt1) – Heavy proteinuria (+sFlt1) – Glomerular endotheliosis (+sFlt1) Placental ischemia may serve as a key stimulus for AT 1 -AA production during pregnancy AT 1 -AAs = potential therapeutic target Zhou et al. Nat Med (8):

Parikh, Karumanchi. Nat Med (8):