Angiotensin-(1-7) attenuates damage to podocytes induced by preeclamptic serum through MAPK pathways

Abstract

The underlying mechanisms of proteinuria, a main characteristic of preeclampsia (PE), have not yet been fully elucidated. Evidence indicates that the renin-angiotensin system (RAS) is involved in the pathogenesis of this disease, including decreased angiotensin-(1-7) [Ang-(1-7)] levels in the circulation and urine. In the present study, we examined the damage to podocytes induced by preeclamptic serum and the effects of Ang-(1-7) on podocytes treated with preeclamptic serum, as well as the underlying mechanisms. The podocytes were incubated with serum obtained from women with PE or with serum from women with normal pregnancies for different periods of time. Cell viability was determined by CCK-8 assay. The cells were treated with various concentrations of Ang-(1-7) and A779 [an (Ang-(1-7) antagonist]. The effects of Ang-(1-7) on the expression of podocyte-specific proteins [nephrin, Wilms tumor‑1 (WT-1) and podocin] and the phosphorylation of mitogen-activated protein kinases (MAPKs) were investigated by western blot analysis. Changes in F-actin rearrangement were determined by immunofluorescence. Podocyte apoptosis was determined by flow cytometry. The results revealed that in the cultured podocytes incubated with preeclamptic serum, there was a decrease in the expression of podocyte-specific proteins (nephrin and WT-1 but not podocin), a rearrangement of F-actin and apoptosis compared with the control group. However, treatment with Ang-(1-7) attenuated podocyte injury in the preeclamptic group, which may be mediated through the downregulation of MAPK (p38, ERK1/2 and JNK) phosphorylation. Thus, our data suggest that Ang-(1-7) plays a protective role in PE through the downregulation of MAPK phosphorylation.

Angiotensin II Type I Receptor Agonistic Autoantibody Induces Podocyte Injury via Activation of the TRPC6- Calcium/Calcineurin Pathway in Pre-Eclampsia

“…To identify the possible novel mechanism underlying TRPC6-calcium/calcineurin signaling activation induced by AT1-AA, we detected the expression of ERK1/2. AT1-AA increased ERK1/2 protein expression, which is in agreement with our previous study [33]. When ERK1/2 inhibitor was administered in the podocytes treated with AT1-AA, we observed marked ameliorations in podocyte injury and a reduction of TRPC6; however, the expression of ERK1/2 was unrecognizable when we knocked down TRPC6.…”

Regulation of insulin sensitivity, insulin production, and pancreatic β cell survival by angiotensin-(1-7) in a rat model of streptozotocin-induced diabetes mellitus

“…Moreover, Ang-(1-7) treatment resulted in a significant decline in the expression and cleavage of caspase-3, a hallmark of apoptosis [28], in the pancreas. The antiapoptotic activity of Ang-(1-7) has also been described in other types of cells, such as human umbilical vein endothelial cells [33], podocytes [29], and alveolar epithelial cells [30].…”

Metadherin facilitates podocyte apoptosis in diabetic nephropathy

“…15, 16, 37 In addition, the p38 MAPK pathway was shown to have an important role in podocyte injury. 38, 39 The data obtained in this study showed that the expression of p-p38 is significantly enhanced in the DN glomeruli and HG-induced MPC5 cells, and it is accompanied by the increase in the expression of Bax and cleaved caspase 3. The inhibition of Mtdh led to the suppression of the activation of p38 MAPK pathway following the HG treatment, which suggests a possible link between Mtdh and p38 MAPK activation.…”