Evaluation of Klotho gene expression and NGAL levels following acute kidney injury during pregnancy hypertensive disorders

Hypertensive disorder during pregnancy (HDP) is the most common complication in obstetrics and is known to lead to death in some pregnant women and/or their fetuses. According to US statistics on maternal mortality rates, HDP accounts for 18 % of all maternal deaths globally [1], while in China, HDP accounts for 10 % of all maternal deaths and is the second leading cause of maternal mortality.[1] Moreover, the proportion of fetal deaths associated with HDP in Latin America and Africa are 9.1 % and 18 %, respectively [2].

Hypertensive disorder is a common cause of Acute Kidney Injury (AKI) during pregnancy [2]. In China, the incidence of Pregnancy-Related Acute Kidney Injury (PR-AKI) is 0.02 %-1.84 % and the still birth death toll following PR-AKI is 27 % [3]. While it has been suggested that 81.9 % of patients with a PR-AKI prognosis will improve, 4.5 % of patients are expected to experience continued renal function deterioration. Positive treatment of PR-AKI can improve a mother's prognosis, but the outcome of PR-AKI is generally poor [3], making PR-AKI a significant concern that obstetricians and nephrologists need to be highly vigilant of.

The pathogenesis of AKI is complex and includes apoptosis, necrosis, oxidative stress, vascular endothelial dysfunction, and inflammation. Previous animal model research on AKI utilizing ureteral obstruction [4], sepsis [5], ischemia–reperfusion [6] or treatments with nephrotoxic drugs [7] has identified Klotho (KL) protein and has indicated that the down-regulation of renal KL was a common phenomenon related to ischemia, oxidative stress, exposure to nephrotoxic drugs and/or AKI in these models. KL is mainly expressed in the kidney and brain and has been found to be closely related to kidney disease, where the expression of KL in human kidneys reduces significantly with the severity of AKI and has been associated with poor short-term prognosis [8]. However, the relationship between KL and AKI has not been fully elucidated, especially in relation to pregnancy related hypertensive disorder. A significant amount of research has targeted the role of KL in AKI [7], [8], [9], [10], hypertension [11], [12] or pregnancy-related diseases [13], [14], but these investigations have been predominantly independent studies and the role of KL in hypertensive disorder-related AKI during pregnancy remains unknown.

KL protein is believed to have anti-oxidative effects that are important to its role in hypertension [15], [16]. In spontaneously hypertensive rats, for example, KL has been found to significantly reduce aorta NADPH oxidase (Nox) activity and to reduce aortic and renal reactive oxygen species, as well as Nox2 (Nox catalytic subunit) protein production [11]. Moreover, transgenic mice that express KL at high levels survive longer than wild-type mice when given a lethal dose of paraquat (which produces large amounts of reactive oxygen species) [16]. However, these anti-oxidative properties are modulated by oxidative stress through a variety of mechanisms, including genetic expression, which leads to reduced KL-mRNA and KL protein levels in response to oxidative stress [15], [16], [17]. This suggests that the role of KL in PR-AKI is modulated by its levels of genetic expression.

To elucidate the relationship between Klotho, oxidative stress and AKI during pregnancy hypertension complications, this study evaluated the expression of the Klotho gene/protein, levels of Neutrophil gelatinase-associated lipocalin (NGAL), a member of the lipocalin superfamily found in neutrophil peroxidase particles and a common biomarker of AKI [18], [19], [20], [21], [22] and the presence of malondialdehyde (MDA) and activity of superoxide dismutase (SOD), as common biomarkers of oxidative damage and stress, respectively, in the blood/serum of pregnant women with hypertensive disorder pregnancy complications, such as AKI. NGAL is expressed at low levels in human lung and kidney and its expression is closely related to the degree of renal injury, with the expression of NGAL being 1000 times greater in the kidney following AKI then the expression of NGAL in a healthy kidney [19]. Moreover, NGAL expression is a potential risk factor for increased oxidative stress following hemodialysis [20], suggesting that NGAL, MDA and SOD are appropriate biomarkers to explore the pathogenesis of AKI in HDP complications as they pertain to KL levels. This work was performed to provide a basis for early diagnosis, to improve maternal and child prognosis, and to promote prenatal and postnatal care.

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