PE is a clinical phenotype in pregnant women associated with unrestricted activation of the inflammatory response. Prior shreds of evidence have suggested a substantial role of many inflammatory mediators (including cytokines) in promoting the pathogenesis of PE. However, other biomolecules in pregnant women with distinct physiological functions during pregnancy should also be simultaneously looked at to understand the pathophysiology of PE in detail. Among other biologically relevant molecules, catecholamine levels have been found to be enhanced in pre-eclamptic women . Catecholamines are degraded by different monoamine oxidases, and renalase is therefore presumed to play a role in regulating the pathogenesis of PE.
Before examining the role of renalase during PE, we analyzed the baseline characteristics in three categories of study populations. Table-1 clearly showed a significant reduction in the duration of gestation, the percentage of vaginal delivery, and fetal birth weight in subjects with PE as compared to healthy pregnant women. On the other hand, pre-eclamptic women demonstrated an increased body mass index (BMI), percentage of caesarian section, systolic and diastolic blood pressure, WBC count, serum urea, and uric acid levels as compared to healthy controls. All these data are in accordance with the previous report .
Importantly, the glomerular filtration rate (GFR) was found to be significantly lower in subjects with PE as compared to healthy pregnant women. Many earlier reports are supporting our results , . It is assumed that the decreased GFR in pre-eclamptic subjects may be due to reduced renal blood flow that results due to high renal vascular resistance. An earlier study demonstrated that the decreased GFR in PE subjects is due to a fall in renal blood flow and a reduction in the ultrafiltration coefficient in glomerular capillary .
A significant elevation of serum renalase was noticed in pregnant women with healthy gestations as compared to those without pregnancy. Additionally, the level of the enzyme was significantly diminished in subjects with PE. The overall results of the present investigation were in line with previous observations [12, 20]. However, our results are in contrary to a report in Pakistani PE patients , that demonstrated comparable renalase levels among subjects with PE, healthy pregnant women, and non-pregnant controls. Discrepancies among studies can be attributed to a lower number of subjects enrolled in the reports from the Pakistan population (non-pregnant controls: n = 30, healthy pregnant women: n = 45, and subjects with PE: n = 20). Compared to the earlier report , in the present study, we enrolled sufficiently large numbers of samples, further strengthing our observations.
Renalase is secreted into the peripheral circulation, and its levels are regulated by renal function and catecholamine concentrations . Prior pieces of evidence support the occurrence of systemic and renal hemodynamic alterations during pregnancy . During pregnancy, systemic renal vasodilation is associated with a 30–40% rise in renal blood flow and GFR . Therefore, a higher level of renalase in pregnant subjects in our study may be due to increased GFR.
A notable reduction in renalase level in preeclamptic women was observed in the present study when compared to the healthy pregnancies. Previously, it was shown that the manipulation of gonadotropin-releasing hormone (GnRH) might alter the expression of renalase and GnRH antagonists downregulate the renalase secretion . As the placenta has a central role in PE , ischemic changes observed during PE possibly accompany low GnRH level and diminish GnRH would facilitate a low level of renalase in pre-eclamptic women.
Prior evidence from both animal and human suggested a regulatory role of renalase on blood pressure . Further, renalase deficiency was found to be associated with hypertension and increased sympathetic activity . Notably, in patients showing resistance to hypertension, the plasma levels of renalase are inversely associated with systolic blood pressure . Our study indicates an inverse association of renalase level with systolic as well as diastolic blood pressure in study subjects. Collectively, all this evidence strongly demonstrated the regulatory importance of renalase with blood pressure.
We found a direct correlation of serum renalase level with GFR. Prior studies have indicated a direct correlation of GFR with renal mass . Additionally, it is also known that the release of renalase into peripheral blood can be influenced by renal function performance. Since GFR is known as the best index for examining renal function, we speculate the direct relationship of GFR with renalase level. Overall, the results of our investigation and earlier reports highlighted an important pathophysiological relevance of serum renalase in the development of PE.
Genetic association studies on the association of common renalase variants with susceptibility to PE is minimal. To date, two independent studies in Turkish  and the Iranian population  have demonstrated the importance of renalase mutants on predisposition to PE development. In the present report, we observed a significant association of homozygous mutant (GG) and minor allele (G) of rs 10887800 and rs2576178 polymorphisms with risk for development of PE in the Chinese population. These observations are following earlier reports, including Iranian  and Turkish patients . However, Bagci et al. failed to demonstrate the association of rs2576178 polymorphism with PE. Furthermore, G-G haplotype (rs10887800-rs2576178) has been associated with susceptibility to PE risk in Iranian patients. Similarly, in the current report rs10887800-G rs2576178-G rs2296545-C haplotype was linked with predisposition to PE when compared to women with or without pregnancy. Our present study is more advantages over the previous report: i) we have included three SNPs of the renalase gene, and ii) normotensive non-pregnant and normotensive pregnant women were enrolled as controls. Collectively results of the present report and earlier studies further strengthn association of renalase polymorphisms with susceptibility to PE.
As we observed significant associations of renalase gene polymorphisms with susceptibility to PE development, further, we analyze the functional relevance of those studied SNPs. Elevated serum renalase was observed in homozygous genotype compared to wild type and heterozygous mutant for rs10887800 and rs2576178 polymorphisms. In contrast, an earlier report highlighted the association of elevated renalase levels in the GG genotype of rs10887800 compared to AA genotype and nonexistence of the relationship between rs2576178 polymorphism and plasma renalase levels in patients undergoing hemodialysis . Also, an earlier report showed an association of high SBP and DBP with GG genotype of rs10887800 polymorphism and for GG genotype of rs2576178 only with SBP. However, in the present study, we did not observe any association of renalase polymorphisms with SBP, DBP, and GFR levels in patients and controls.