Erythropoietin (EPO) has been shown to exert cytoprotective effects on erythroid progenitor cells as well as various non-erythroid cells. Experimental studies have demonstrated the renoprotective effects of EPO in various acute and chronic renal injury models. These protective effects have been largely attributed to antiapoptotic signalings of EPO. However, injured cells undergoing apoptosis are generally too severely damaged to function properly. Therefore, simply corrupting apoptotic pathway is unlikely to be an effective strategy, because the remaining damaged cells may not function appropriately, or they may eventually undergo necrotic cell death. Recent evidences suggest that EPO also provides cytoprotection by ameliorating oxidative stress, the principal cellular insult. EPO may exert its antioxidative effects directly by exploiting intracellular antioxidative mechanisms such as heme oxygenase-1 and glutathione peroxidase. In addition, EPO may act indirectly by inducing iron depletion and thereby inhibiting iron-dependent oxidative injury. Increasing red blood cells by EPO may also indirectly reduce cellular oxidative stress, as red blood cells are loaded with a substantial amount of antioxidative enzymes. Further investigation regarding the mechanisms of cellular antioxidative responses to EPO would provide a better insight to cytoprotective action of EPO, and would support the development of better cytoprotective drugs in the near future.
Previous in vitro studies indicated that aldosterone nongenomically phosphorylates epidermal growth factor receptor (EGFR) through activation of upstream signals, heat shock protein 90β (Hsp90β), and cytosolic (c)-Src kinase. We demonstrated that aldosterone rapidly elevates EGFR phosphorylation in rat kidney. There are no in vivo data regarding renal Hsp90(α and β) and phosphorylated (p)c-Src protein expressions. The present study further investigates the expressions of these proteins. Male Wistar rats were intraperitoneally injected with normal saline solution or aldosterone (Aldo: 150 μg/kg BW). After 30 minutes, abundances and localizations of these proteins were determined. Aldosterone enhanced renal Hsp90β protein abundance (P < 0.001), but Hsp90α and pc-Src protein levels remained unaltered. Expression of Hsp90(α and β) was induced prominently in the proximal convoluted tubules (PCTs). Activation of Hsp90α was observed in vascular and outer medulla regions, whereas Hsp90β was induced in the cortex. Immunoreactivity of pc-Src was elevated in PCT with obvious staining at the luminal membrane. This in vivo study is the first to demonstrate that aldosterone nongenomically elevates Hsp90(α and β) protein expressions in rat kidney. Aldosterone had no effect on pc-Src protein levels but modulated localization. These results indicate that aldosterone regulates upstream mediators of EGFR transactivation in vivo.
Previous in vitro studies demonstrated that aldosterone rapidly activates sodium-hydrogen exchangers 1 and 3 (NHE 1 and 3). In vitro investigations revealed that protein kinase C (PKC) regulates NHE properties. We previously demonstrated that aldosterone rapidly enhances PKCα protein abundance in the rat kidney. There are no reports of renal PKCβ (I and II) protein levels related to the regulation by aldosterone. There are also no in vivo data regarding the rapid effects of aldosterone on renal protein levels of NHE (1 and 3) and PKCβ (I and II), simultaneously. In the current study, rats received normal saline solution or aldosterone (150 μg/kg BW, i.p.). After 30 minutes, abundance and immunoreactivity of these proteins were determined by Western blot analysis and immunohistochemistry, respectively. Aldosterone increased NHE1 and NHE3 protein abundance to 152% and 134%, respectively (P < 0.05). PKCβI protein level was enhanced by 30%, whereas PKCβII declined slightly. Aldosterone increased NHE protein expression mostly in the medulla. PKCβI immunostaining intensity was increased in the glomeruli, renal vasculature, and thin limb of the loop of Henle, while PKCβII was reduced. This is the first in vivo study to simultaneously demonstrate that aldosterone rapidly elevates PKCβI and NHE (1 and 3) protein abundance in the rat kidney. Aldosterone-induced NHE (1 and 3) protein levels may be related to PKCβI activation.
Background: In vitro studies have demonstrated that aldosterone elicits nongenomic actions by enhancing protein expressions of phosphorylated epidermal growth factor receptor (pEGFR) and phosphorylated extracellular signal-regulated kinases 1/2 (pERK1/2). There are no available in vivo investigations regarding this action of aldosterone on renal pEGFR-pERK1/2 protein expressions. Methods: Male Wistar rats received normal saline solution, low-dose (LA: 150 µg/kg BW) or high-dose aldosterone (HA: 500 µg/kg BW) by intraperitoneal injection. After 30 min, protein abundances and localizations of renal pEGFR and pERK1/2 were determined by Western blot and immunohistochemistry. Results: Plasma aldosterone levels were increased in LA and HA groups (p < 0.001). Aldosterone enhanced renal pEGFR and pERK1/2 protein abundances (p < 0.001). HA showed a greater stimulation on pEGFR immunoreactivity than LA in the glomerulus, vasa recta, and thin limb of Henle’s loop in the inner medulla area. LA provided more reactivity of pERK1/2 in the thick ascending limb of Henle’s loop, outer medullary collecting duct, and proximal straight tubule, whereas HA illustrated more pERK1/2 activation in the glomerulus, peritubular capillary, and inner medulla region. Conclusion: This is the first in vivo study which demonstrates that aldosterone, via the nongenomic pathway, could elevate pEGFR and pERK1/2 protein abundances and expressions in the rat kidney. These results indicate that aldosterone induces phosphorylation of EGFR upstream of ERK1/2.
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