New Insight into the Molecular Drug Target of Diabetic Nephropathy

Soetikno, Vivian; Arozal, Wawaimuli; Louisa, Melva; Setiabudy, Rianto

doi:10.1155/2014/968681

Cited by 28 publications

(21 citation statements)

References 104 publications

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“…1C). As WT-1 is a marker of podocytes and expressed in the nucleus [32-34], the above results indicate that swiprosin-1 was expressed in podocytes of mouse renal glomeruli. As shown in Fig.…”

Section: Resultsmentioning

confidence: 94%

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

Wang

et al. 2018

Cell Physiol Biochem

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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.

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Section: Resultsmentioning

confidence: 94%

“…Down-regulation of podocyte-specific proteins is an indicator of podocyte injury [32]. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

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

Wang

et al. 2018

Cell Physiol Biochem

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“…The development of diabetic nephropathy is a complex process: proteases, growth factors, cytokines, and chemokines are released from renal cells and interact with each other to promote neovascularization and fibrosis. 35,36 Dysfunction and morphological changes in glomeruli, such as hypertrophy, increased glomerular Ig uptake, and mesangial matrix expansion in early stages, are associated with the progress of diabetic nephropathy. 4 Serum LPA levels are increased in high-fat, diet-induced diabetic mice, 20 and the expression of ATX, an enzyme for LPA synthesis, is increased in the kidneys of diabetic db/db mice.…”

Section: Discussionmentioning

confidence: 99%

Blocking lysophosphatidic acid receptor 1 signaling inhibits diabetic nephropathy in db/db mice

Choi

et al. 2017

Kidney International

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Lysophosphatidic acid (LPA) is known to regulate various biological responses by binding to LPA receptors. The serum level of LPA is elevated in diabetes, but the involvement of LPA in the development of diabetes and its complications remains unknown. Therefore, we studied LPA signaling in diabetic nephropathy and the molecular mechanisms involved. The expression of autotaxin, an LPA synthesis enzyme, and LPA receptor 1 was significantly increased in both mesangial cells (SV40 MES13) maintained in high-glucose media and the kidney cortex of diabetic db/db mice. Increased urinary albumin excretion, increased glomerular tuft area and volume, and mesangial matrix expansion were observed in db/db mice and reduced by treatment with ki16425, a LPA receptor 1/3 antagonist. Transforming growth factor (TGF)β expression and Smad-2/3 phosphorylation were upregulated in SV40 MES13 cells by LPA stimulation or in the kidney cortex of db/db mice, and this was blocked by ki16425 treatment. LPA receptor 1 siRNA treatment inhibited LPA-induced TGFβ expression, whereas cells overexpressing LPA receptor 1 showed enhanced LPA-induced TGFβ expression. LPA treatment of SV40 MES13 cells increased phosphorylated glycogen synthase kinase (GSK)3β at Ser9 and induced translocation of sterol regulatory element-binding protein (SREBP)1 into the nucleus. Blocking GSK3β phosphorylation inhibited SREBP1 activation and consequently blocked LPA-induced TGFβ expression in SV40 MES13 cells. Phosphorylated GSK3β and nuclear SREBP1 accumulation were increased in the kidney cortex of db/db mice and ki16425 treatment blocked these pathways. Thus, LPA receptor 1 signaling increased TGFβ expression via GSK3β phosphorylation and SREBP1 activation, contributing to the development of diabetic nephropathy.

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“…However, effective clinical interventions for DN have not yet been elucidated. Although great advances have been accomplished in tight glycemic control and blood pressure control [5, 6], they cannot stop DN progression.…”

Section: Introductionmentioning

confidence: 99%

EGFR inhibition attenuates diabetic nephropathy through decreasing ROS and endoplasmic reticulum stress

Zhao

Zhong

et al. 2017

Oncotarget

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Diabetic nephropathy (DN) is a progressive kidney disease due to glomerular capillary damage in diabetic patients. Endoplasmic reticulum (ER) stress caused by reactive oxygen species (ROS) is associated with DN progression. Epidermal growth factor receptor (EGFR) mediates oxidative stress and damage of cardiomyocytes in diabetic mice. Here we demonstrated that AG1478, a specific inhibitor of EGFR, blocked EGFR and AKT phosphorylation in diabetic mice. Oxidative stress and ER stress markers were eliminated after AG1478 administration. AG1478 decreased pro-fibrotic genes TGF-β and collagen IV. Furthermore, we found that high glucose (HG) induced oxidative stress and ER stress, and subsequently increased ATF4 and CHOP. These changes were eliminated by either AG1478 or ROS scavenger N-acetyl-L-cysteine (NAC) administration. These results were confirmed by knock-down approaches in renal mesangial SV40 cells. However, AG1478, not NAC, reversed HG induced EGFR and AKT phosphorylation. These results suggest that EGFR/AKT/ROS/ER stress signaling plays an essential role in DN development and inhibiting EGFR may serve as a potential therapeutic strategy in diabetic kidney diseases.

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New Insight into the Molecular Drug Target of Diabetic Nephropathy

Cited by 28 publications

References 104 publications

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

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

Blocking lysophosphatidic acid receptor 1 signaling inhibits diabetic nephropathy in db/db mice

EGFR inhibition attenuates diabetic nephropathy through decreasing ROS and endoplasmic reticulum stress

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