Swiprosin-1 Promotes Mitochondria-Dependent Apoptosis of Glomerular Podocytes via P38 MAPK Pathway in Early-Stage Diabetic Nephropathy

Abstract

Background/Aims: Podocyte injury, especially podocyte apoptosis, plays a major role in early-stage diabetic nephropathy (DN). Swiprosin-1, also known as EF hand domain containing 2 (EFhd2), is a Ca²⁺-binding protein in different cell types. However, the function of swiprosin-1 in podocytes remains unknown. Methods: The expression and distribution of swiprosin-1 were investigated in the mouse renal glomerulus and conditionally immortalized mouse podocyte cell line MPC-5. The expression of swiprosin-1 was also detected in streptozotocin (STZ)-treated mice and MPC-5 cells treated with high glucose (HG). Nephrin and podocin were detected by immunohistochemistry and immunofluroscence. Collagen IV, transforming growth factor-β (TGF-β) and fibronectin mRNA expressions were assayed by real-time PCR. Apoptotic proteins and phosphorylation of p38 mitogen-activated protein kinase (MAPK) were detected by immunoblotting. Results: Swiprosin-1 was found to be expressed in podocytes of the mouse glomerulus and MPC-5 cells. Swiprosin-1 expression was increased in STZ-treated mice and MPC-5 cells treated with HG. In Swiprosin-1-/- diabetic mice, kidney/ body weight, urinary albumin, podocyte foot process effacement and glomerular basement membrane thickening were attenuated; the downregulation of nephrin and podocin expression in the glomerulus was inhibited; and the upregulation of collagen IV, TGF-β and fibronectin mRNA expression in the renal cortex was ameliorated as compared with those in diabetic swiprosin-1+/+ mice. In addition, the increased apoptosis of podocytes, proapoptotic protein expression and p38 phosphorylation in Swiprosin-1-/- diabetic mice were inhibited as compared with those in diabetic swiprosin-1+/+ mice. Knockdown of swiprosin-1 in MPC-5 cells reduced the apoptosis of podocytes, proapoptotic protein expression and p38 phosphorylation induced by HG. Targeted knockdown of p38 attenuated the increased apoptosis of MPC-5 cells over-expressing swiprosin-1. Conclusion: Swiprosin-1 expression in podocytes of the mouse glomerulus played a critical role in early-stage DN. Swiprosin-1 deficiency in early DN attenuated mitochondria-dependent podocyte apoptosis induced by hyperglycemia or HG via p38 MAPK signaling pathway.

Conserved Noncoding Sequences Boost ADR1 and SP1 Regulated Human Swiprosin-1 Promoter Activity

“…6C–E ). Taken together, our present results correlated to the transcription (mRNA) of Swiprosin-1 gene was upregulated upon treatments, which were previously reported in mast cells, T cells, malignant melanoma cells 1 , macrophage, and glomerular endothelial cells 6 , 9 , 20 . More importantly, we notified that all CNS-1, -2 and -3 upregulate the transactivation of −141 bp proximal promoter region of Swiprosin-1 compared with the -141/Sw-1 alone (without conjugated with CNS) even in the absence of above treatments, and CNS-3 was most predominant among them (Fig.…”

“…This result was correlated with that the Swiprosin-1gene expression was not upregulated in mouse B cells upon anti-IgM F(ab)2/IL-4, LPS or anti-CD40/IL-4 12 . However, our previous studies and others reported that endogenous Swiprosin-1gene expression was specifically upregulated in human mast and T cells up on PMA or A23187 or PMA/A23187 stimulation and also in malignant melanoma cells upon EGFR stimulation 2 , 6 , 7 , 9 , 11 . Swiprosin-1 gene expression was very broad and also its expression level was tissue or cell type specific of various organisms 1 , 9 , 19 , 20 .…”

“…Swiprosin-1 deficiency reduces mitochondria-dependent podocyte apoptosis, induced by hyperglycemia or high glucose, via p38 MAPK signaling pathway in the early stage of diabetic nephropathy 9 . Swiprosin-1 plays a critical role in the macrophage immune response to LPS- and cecal ligation and puncture-induced sepsis, as well as in the production of inflammatory cytokines like IL-1b, IL-6, TNF-a, IL-10, and IFN-g.…”

Dexmedetomidine Ameliorates Acute Stress‐Induced Kidney Injury by Attenuating Oxidative Stress and Apoptosis through Inhibition of the ROS/JNK Signaling Pathway

“…The kidney is composed of tubules, renal vesicles, and glomeruli. Studies have reported that kidney injury is mainly caused by glomerular or tubular apoptosis [ 53 , 54 ]. However, whether DEX alleviates apoptosis induced by acute stress in tubular cells or glomerular cells is unclear.…”

Network Pharmacology-based Prediction of Mechanism of Shenzhuo Formula for Application to DN

“…As shown in the GO enrichment analysis results, the potential targets of shenzhuo formula acting on DN were mainly associated with various biological processes, such as lipopolysaccharide-mediated signaling pathway, inflammatory response, positive regulation of cyclase activity, protein kinase B signaling, positive regulation of MAP kinase activity, response to estradiol, which have a strongly direct correlation with the pathogenesis of DN [28][29][30][31][32][33][34].…”