Albumin induces CD44 expression in glomerular parietal epithelial cells by activating extracellular signal‐regulated kinase 1/2 pathway

Abstract

De novo expression of CD44 in glomerular parietal epithelial cells (PECs) leads to a prosclerotic and migratory PEC phenotype in glomerulosclerosis. However, the regulatory mechanisms underlying CD44 expression by activated PECs remain largely unknown. This study was performed to examine the mediators responsible for CD44 induction in glomerular PECs in association with diabetes. CD44 expression and localization were evaluated in the glomeruli of Zucker diabetic rat kidneys and primary cultured PECs upon albumin stimulation. Real-time polymerase chain reaction confirmed an albuminuria-associated upregulation of the CD44 gene in the glomeruli of diabetic rats. Immunostaining analysis of diabetic kidneys further revealed an increase in CD44 in hypertrophic PECs, which often contain albuminpositive vesicles. Losartan treatment significantly attenuated albuminuria and lowered CD44 protein levels in the diabetic kidneys. In primary cultured rat PECs, rat serum albumin (0.25-1 mg/ml) caused a dose-dependent upregulation of CD44, claudin-1, and megalin protein expression, which was accompanied by an activation of extracellular signal-regulated kinase1/2 (ERK1/2) signaling. Albumin-induced CD44 and claudin-1 expression were greatly suppressed in the presence of the ERK1/2 inhibitor, U0126. In addition, knockdown of megalin by small interfering RNA interference in PECs resulted in a significant reduction of albumin-induced CD44 and claudin-1 proteins. Taken together, our results demonstrate that albumin induces CD44 expression by PECs via the activation of the ERK signaling pathway, which is partially mediated by endocytic receptor megalin. K E Y W O R D S albuminuria, diabetic glomerular disease, megalin, parietal epithelial cells (PECs), U0126

Kidney Injury Molecule-1 Is Upregulated in Renal Lipotoxicity and Mediates Palmitate-Induced Tubular Cell Injury and Inflammatory Response

“…Moreover, activation of the ERK1/2 signaling pathway is also required for palmitate-induced OPN and CD44 in renal tubular epithelial cells. These results are in agreement with previous reports showing that ERK1/2 regulates mouse KIM expression physiologically and following ischemic and septic renal injury [26] and that activated ERK1/2 increases CD44 in glomerular parietal epithelial cells [34,35]. Although our in vitro findings support that palmitate may induce the production of inflammatory mediators through the ERK signaling pathway, further in vivo studies are required to examine the signaling pathways involved in lipid overload-related tubular cell injury and inflammatory gene expression in proteinuric kidney disease.…”

Genetics and phenotypic heterogeneity of Dent disease: the dark side of the moon

“…ClC-5, megalin and cubilin positivity was identified in human PECs too (Gianesello et al 2018), expanding the spectrum of possible causes of glomerulosclerosis in patients with Dent disease. It was also shown that rat and murine PECs could internalize albumin under normal and overload conditions, in vivo and in vitro (Zhao et al 2019), suggesting a role for ClC-5 in albumin uptake in these cells as well.…”

Albumin Reduces Oxidative Stress and Neuronal Apoptosis via the ERK/Nrf2/HO‐1 Pathway after Intracerebral Hemorrhage in Rats

“…Our previous quantitative proteomics study [ 23 ] showed that the ERK1 and ERK2 cascades were the top two biological processes after ICH and that the albumin and ERK1/2 signaling pathways were the top protein-protein interaction networks. Recently, some studies showed that there was an important link between albumin and the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase, ERK1/ERK2 in kidney disease, and ERK1/2 signaling pathway was the downstream signal activated by albumin therapy [ 24 , 51 ]. Reich et al found that albumin-activated ERK via EGF receptor in human renal epithelial cells and the generation of ROS after albumin exposure was an important proximate event in the albumin-induced cell signaling [ 52 ].…”

“…Extracellular signal-regulated kinase (ERK) 1/2, a prototypic subfamily of MAPKs, is considered the top biological factor that participates in oxidative and ER stress [23]. Albumin therapy activates the downstream protein ERK1/2 signaling [24,25]. Previous studies showed that nuclear factor erythroid-related factor 2 (Nrf2) is activated by phosphorylate-ERK1/2 (p-ERK1/2) [26], and Nrf2 then enters the nucleus to promote the transcription of the antioxidantresponsive element-regulated gene heme oxygenase-1 (HO-1), which plays a protective role in cellular defense against OS after ICH [27][28][29].…”