Midkine Regulates BP through Cytochrome P450–Derived Eicosanoids

Sato, Yuka; Sato, Waichi; Maruyama, Shoichi; Wilcox, Christopher S.; Falck, John R.; Masuda, Tomohiro; Kosugi, Tomoki; Kojima, Hiroshi; Maeda, Kayaho; Furuhashi, Kazuhiro; Ando, Masahiko; Imai, Enyu; Matsuo, Seiichi; Kadomatsu, Kenji

doi:10.1681/asn.2013121259

Cited by 11 publications

(7 citation statements)

References 54 publications

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“…Serum creatinine (Cr), the ratio of albumin to Cr in urine, and systolic blood pressure were measured as described previously. 30,31 Plasma and urinary Bsg levels were measured using commercial enzyme-linked immunosorbent assay kits according to the respective instructions from the manufacturers (R&D Systems, Minneapolis, MN). Measured levels in urine were…”

Section: Animals and Experimental Designmentioning

confidence: 99%

CD147/Basigin Deficiency Prevents the Development of Podocyte Injury through FAK Signaling

Yoshioka

Kosugi

Masuda

et al. 2019

The American Journal of Pathology

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Podocytes, which are susceptible to injury by various stimuli and stress, are critical regulators of proteinuric kidney diseases, regardless of the primary disease and pathogenesis. We further confirmed a significant correlation between urinary CD147/basigin (Bsg) levels and proteinuria in patients with focal segmental glomerulosclerosis. However, the molecular mechanism of podocyte injury involving Bsg is not fully understood. Here, the involvement of Bsg in the pathogenesis of podocyte injury was elucidated. Healthy podocytes rarely express Bsg protein. In two independent mouse models, including adriamycin-induced nephropathy and N u -nitro-L-arginine methyl ester (L-name)-induced endothelial dysfunction, Bsg induction in injured podocytes caused podocyte effacement, which led to development of proteinuria. Bsg silencing in cultured podocytes exposed to transforming growth factor-b suppressed focal adhesion rearrangement and cellular motility via the activation of b 1 integrinefocal adhesion kinaseematrix metallopeptidase signaling. In addition, induction of vascular endothelial growth factor and endothelin-1, which are implicated in podocyte-to-endothelial cross-communication, was lower in the supernatants of cultured Bsg-silenced podocytes stimulated with transforming growth factor-b. In this setting, Bsg may be involved in a physiological positive feedback loop that accelerates podocyte cell motility and depolarization. The current study thus suggests that Bsg silencing via suppression of b 1 integrinefocal adhesion kinaseematrix metallopeptidase signaling may be an attractive therapeutic strategy for the maintenance of podocytes in patients with proteinuric kidney diseases.

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Section: Animals and Experimental Designmentioning

confidence: 99%

CD147/Basigin Deficiency Prevents the Development of Podocyte Injury through FAK Signaling

Yoshioka

Kosugi

Masuda

et al. 2019

The American Journal of Pathology

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“…To date, MK blockade has been shown to improve hypertension in ischemic renal injury through regulation of the renin-angiotensin system. 31,32 Accordingly, an MK-regulated device may lead to a reduction in toxicity from LN therapy. Herein, to our knowledge, we demonstrated for the first time that MK induces NFATregulated activation of T cells and Th1 cell differentiation through IL-12/STAT4 signaling, leading to the exacerbation of LN ( Figure 6).…”

Section: Discussionmentioning

confidence: 99%

“…Western blot analysis was performed as described previously. 31 The blots were incubated with goateanti-mouse MK Ab, 32 monoclonal antieb-actin Ab (Sigma-Aldrich, St. Louis, MO), rabbiteanti-mouse NFAT1 Ab, histone-H3 Ab, glyceraldehyde-3-phosphate dehydrogenase Ab, STAT1 Ab, phospho-STAT1 Ab, STAT4 Ab (all from Cell Signaling Technology, Danvers, MA), and phospho-NFATc2 Ab (Santa Cruz Biotechnology); and mouse monoclonal anti-mouse phospho-STAT4 Ab (Santa Cruz Biotechnology), followed by incubation with peroxidase-conjugated anti-goat IgG, mouse IgG, and rabbit IgG (Jackson Immunoresearch Laboratories, West Grove, PA). The protein signals were visualized with an Amersham Imager 600 (GE Healthcare, Little Chalfont, United Kingdom).…”

Section: Western Blot Analysismentioning

confidence: 99%

Growth Factor Midkine Promotes T-Cell Activation through Nuclear Factor of Activated T Cells Signaling and Th1 Cell Differentiation in Lupus Nephritis

Masuda

Maeda

Sato

et al. 2017

The American Journal of Pathology

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Activated T cells play crucial roles in the pathogenesis of autoimmune diseases, including lupus nephritis (LN). The activation of calcineurin/nuclear factor of activated T cells (NFAT) and STAT4 signaling is essential for T cells to perform various effector functions. Here, we identified the growth factor midkine (MK; gene name, Mdk) as a novel regulator in the pathogenesis of 2,6,10,14-tetramethylpentadecane-induced LN via activation of NFAT and IL-12/STAT4 signaling. Wild-type (Mdk) mice showed more severe glomerular injury than MK-deficient (Mdk) mice, as demonstrated by mesangial hypercellularity and matrix expansion, and glomerular capillary loops with immune-complex deposition. Compared with Mdk mice, the frequency of splenic CD69 T cells and T helper (Th) 1 cells, but not of regulatory T cells, was augmented in Mdk mice in proportion to LN disease activity, and was accompanied by skewed cytokine production. MK expression was also enhanced in activated CD4 T cells in vivo and in vitro. MK induced activated CD4 T cells expressing CD69 through nuclear activation of NFAT transcription and selectively increased in vitro differentiation of naive CD4 T cells into Th1 cells by promoting IL-12/STAT4 signaling. These results suggest that MK serves an indispensable role in the NFAT-regulated activation of CD4 T cells and Th1 cell differentiation, eventually leading to the exacerbation of LN.

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“…MK is induced by oxidative stress via the activation of hypoxia-inducible factor-1-alpha ( 7 ). The pathological roles of MK in renal disease are broad, ranging from progression of CKD ( 8 ), to hypertension ( 9 ), diabetes mellitus (DM) associated kidney damage ( 10 ) and drug toxicity ( 11 ).…”

Section: Introductionmentioning

confidence: 99%

Midkine: Utility as a Predictor of Early Diabetic Nephropathy in Children with Type 1 Diabetes Mellitus

Metwalley¹,

Farghaly²,

Gabri³

et al. 2021

Jcrpe

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Objective: This study aimed to assess the role of serum midkine (MK) as a biomarker for early detection of diabetic nephropathy in children with type 1 diabetes mellitus (T1DM) before microalbuminuria emerges. Methods: A total of 120 children with T1DM, comprising 60 microalbuminuric patients (Group 1), 60 normoalbuminuric patients (Group 2), and 60 healthy participants as a control group (Group 3) were included. Detailed medical history, clinical examination, and laboratory assessment of high-sensitivity C-reactive protein (hs-CRP), hemoglobin A1c percentage (HbA1c%), lipid profile, urinary albumin to creatinine ratio (ACR), serum MK and estimated glomerular filtration rate based on serum creatinine were performed in all participants. Results: Both Group 1 and Group 2 had significantly higher serum MK compared to controls (p<0.001). Additionally, significantly higher MK concentrations were present in Group 1 compared with Group 2 (p<0.001). Receiver operating characteristic curve analysis revealed that the MK concentration cutoff value of 1512 pg/mL was able to predict microalbuminuria with a sensitivity of 96% and specificity of 92%. Stepwise regression analysis revealed that HbA1c%, hs-CRP, and ACR were independently related to MK levels (p<0.001 for each). Conclusion: The results of this study suggest that serum MK is a useful, novel, practical marker for the evaluation of renal involvement in children with T1DM, especially in normoalbuminuric children.

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Midkine Regulates BP through Cytochrome P450–Derived Eicosanoids

Cited by 11 publications

References 54 publications

CD147/Basigin Deficiency Prevents the Development of Podocyte Injury through FAK Signaling

CD147/Basigin Deficiency Prevents the Development of Podocyte Injury through FAK Signaling

Growth Factor Midkine Promotes T-Cell Activation through Nuclear Factor of Activated T Cells Signaling and Th1 Cell Differentiation in Lupus Nephritis

Midkine: Utility as a Predictor of Early Diabetic Nephropathy in Children with Type 1 Diabetes Mellitus

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