Downregulation of Cullin 3 Ligase Signaling Pathways Contributes to Hypertension in Preeclampsia

Abstract

Background: Preeclampsia (PE) is a leading cause of maternal and perinatal morbidity and mortality; however, its etiology and pathophysiology remain obscure. PE is initiated by inadequate spiral artery remodeling and subsequent placental ischemia/hypoxia, which stimulates release of bioactive factors into maternal circulation, leading to hypertension and renal damage.Methods and Results: Abundance of key components of cullin 3-ring ubiquitin ligase (CRL3), including cullin 3 (CUL3) and its neddylated modification, and adaptors including Kelch-like 2 (KLHL2) and Rho-related BTB domain containing protein 1 was all decreased in spiral arteries and placentas of PE patients. Similar changes were found in aortic tissues and renal distal tubules of pregnant mice treated with Nω-nitro-l-arginine methyl ester hydrochloride. The downregulation of CRL3 function led to accumulation of with-no-lysine kinases, phosphodiesterase 5, and RhoA in vessels and renal distal tubules, which promoted vasoconstriction and Na–Cl cotransporter activation in the distal convoluted tubule (DCT), as well as vascular and DCT structure remodeling. Proton pump inhibitor esomeprazole partially restored CRL3 function. In vitro studies have shown that increased abundance of JAB1, a component of the COP9 signalosome, inhibited CUL3 neddylation and promoted the expression of hypoxia-inducible factor 1α, which downregulated peroxisome proliferator–activated receptor γ and further promoted CUL3 inactivation. KLHL3/2 was degraded by increased autophagy.Conclusion: These findings support that the downregulation of CRL3 function disrupts the balance of vasoconstriction and vasodilation and aggravates excess reabsorption of sodium in PE.

Combined Kelch-like 3 and Cullin 3 Degradation is a Central Mechanism in Familial Hyperkalemic Hypertension in Mice

“…Recent work from the Fenton group suggests neddylation of several cullins, including CUL3 changes in dietary K + intake in mice, 42 (preprint) pointing to a possible role for modulation of JAB1 activity under normal physiologic conditions. Dysregulation of CUL3 neddylation may also contribute to diabetic kidney disease, because KLHL3 abundance is lower in db/db diabetic mice, 14 in streptozotocin-induced type 1 diabetic mice, 15 and in a mouse model of pre-eclampsia, 43 with increased NCC phosphorylation observed in all three models. We also reported that renal tubular Cul3 −/− mice develop renal fibrosis, and that lower CUL3 abundance is observed in several mouse renal injury models 44 .…”

Irregular Expression of Cellular Stress Response Markers in the Placenta of Women with Chronic Venous Disease

“…Here, we propose for future studies a possible implication of non-coding RNAs including micro RNAs (miRNAs) and long non-coding RNAs (lncRNAs), whose relevance in the regulation of oxidative stress and potential translational applications has been previously reported [ 52 , 53 , 54 , 55 ]. However, prior works have also described altered levels of Keap1 and CUL3 in other pregnancy complications, such as preeclampsia, suggesting its potential role in the pathophysiology of obstetric diseases [ 56 , 57 ]. This could entail possible pathophysiological consequences observed in the placenta of women with CVD.…”