Renal Complement Activation in Preeclampsia (page 117)
A growing body of evidence suggests that complement dysregulation plays a role in the pathogenesis of preeclampsia. The kidney is one of the major organs affected in preeclampsia. Penning et al hypothesized that complement activation is involved in the kidney damage in preeclampsia. In this issue, they studied autopsied kidneys from 11 women with preeclampsia, 25 pregnant controls, and 14 nonpregnant controls with hypertension. The samples were immunostained for complement factors and immunoglobulins. All of the kidney sections obtained from the preeclamptic women contained glomerular C4d deposits in a predominantly global staining pattern. Furthermore, preeclampsia was associated with glomerular C1q and IgM, but not with mannose-binding lectin or properdin, indicating classical pathway activation. The results were validated in a soluble fms-like tyrosine kinase-1–induced preeclampsia mouse model. These mice developed excess glomerular C4 deposits and increased levels of circulating activated C3, indicating that preeclampsia-related renal complement activation is initiated by endothelial damage caused by angiogenic dysregulation. The results from this study suggest that inhibiting complement activation could be beneficial for preventing the renal manifestations of preeclampsia. The authors previously found increased classical pathway activation in the placentas of preeclamptic women. Inhibiting excessive complement activation may therefore be a promising therapeutic approach affecting multiple organ systems. However, further investigation is needed to establish the safety of complement inhibition during pregnancy.
Mineralocorticoid Blockade and Aortic Stiffness (page 99)
Women are normally protected against development of cardiovascular disease, but this protection is lost in conditions of insulin resistance, such as obesity and type 2 diabetes mellitus. Data from our laboratory, and that of others, suggest that consumption of a Western diet, high in fat and refined carbohydrates, and associated heightened tissue renin–angiotensin–aldosterone system activity results in attenuated nitric oxide–mediated vasodilation and increased vascular fibrosis and stiffness. This is consistent with clinical observations that obesity, insulin resistance, and diabetes mellitus are predisposing factors for development of vascular stiffness in both men and women. Our current study indicates that low doses of the mineralocorticoid receptor blocker spironolactone, which does not affect blood pressure, prevent Western diet–induced abnormalities in nitric oxide–mediated vasorelaxation and vascular stiffness in women (Figure). These findings have important clinical implications because vascular stiffness is a powerful predictor for the development of cardiovascular disease. Furthermore, these findings suggest that a strategy to reduce mineralocorticoid receptor signaling may be preventative and therapeutic in protecting against development of vascular disease in women.
Neutrophil Gelatinase–Associated Lipocalin Mediates Mineralocorticoids Fibrotic Effects (page 158)
Mineralocorticoid receptor (MR) antagonists showed benefit in cardiovascular diseases, but their mode of action remains poorly understood. Underlying mechanisms may associate diuretic, antifibrotic, and anti-inflammatory effects. Clinical use of MR antagonists presents some limitations related to their renal potassium sparing effect that favors hyperkalemia in patients with renal dysfunction. Understanding the signaling pathways modulated by aldosterone and MR in cardiovascular diseases is required to identify novel targets and biomarkers of MR activation.
In this issue, Tarjus et al report that a novel MR target, neutrophil gelatinase–associated lipocalin (NGAL), has a critical role in high blood pressure and cardiovascular remodeling induced by mineralocorticoid activation: preventing NGAL expression in a murine model blunted cardiovascular extracellular matrix deposition and increased blood pressure. In patients with stage B heart failure, plasma levels of the complex between NGAL and matrix metalloproteinase 9 correlated with fibrosis markers, such as procollagen type I N-terminal peptide. NGAL–matrix metalloproteinase 9 complex levels may be useful as biomarkers of MR activation to select patients prone to MR antagonists and therefore increasing the benefit/risk balance of this therapeutic class.
These data also uncover a novel role of NGAL that has been considered until now as a marker of renal injury but may also have a mechanistic role in cardiovascular disease and beyond. NGAL may be a novel therapeutic target in hypertension and extracellular matrix deposition.
- © 2015 American Heart Association, Inc.