دورية أكاديمية
High glucose-induced downregulation of PTEN-Long is sufficient for proximal tubular cell injury in diabetic kidney disease.
| العنوان: | High glucose-induced downregulation of PTEN-Long is sufficient for proximal tubular cell injury in diabetic kidney disease. |
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| المؤلفون: | Das F; VA Research, South Texas Veterans Health Care System, San Antonio, TX, USA; Department of Medicine, TX, USA., Ghosh-Choudhury N; Department of Pathology, UT Health, San Antonio, TX, USA., Kasinath BS; Department of Medicine, TX, USA., Sharma K; VA Research, South Texas Veterans Health Care System, San Antonio, TX, USA; Department of Medicine, TX, USA., Choudhury GG; VA Research, South Texas Veterans Health Care System, San Antonio, TX, USA; Department of Medicine, TX, USA; Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, USA. Electronic address: choudhuryg@uthscsa.edu. |
| المصدر: | Experimental cell research [Exp Cell Res] 2024 Jul 01; Vol. 440 (1), pp. 114116. Date of Electronic Publication: 2024 Jun 01. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Academic Press Country of Publication: United States NLM ID: 0373226 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2422 (Electronic) Linking ISSN: 00144827 NLM ISO Abbreviation: Exp Cell Res Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Orlando Fl : Academic Press Original Publication: New York, Academic Press. |
| مواضيع طبية MeSH: | Diabetic Nephropathies*/metabolism , Diabetic Nephropathies*/pathology , Diabetic Nephropathies*/genetics , Glucose*/metabolism , Glucose*/pharmacology , Kidney Tubules, Proximal*/metabolism , Kidney Tubules, Proximal*/pathology , Kidney Tubules, Proximal*/drug effects , Mechanistic Target of Rapamycin Complex 1*/metabolism , Mechanistic Target of Rapamycin Complex 1*/genetics , PTEN Phosphohydrolase*/metabolism , PTEN Phosphohydrolase*/genetics, Animals ; Humans ; Male ; Mice ; Down-Regulation/drug effects ; Mice, Inbred C57BL ; Proto-Oncogene Proteins c-akt/metabolism ; Proto-Oncogene Proteins c-akt/genetics ; Signal Transduction |
| مستخلص: | During the progression of diabetic kidney disease, proximal tubular epithelial cells respond to high glucose to induce hypertrophy and matrix expansion leading to renal fibrosis. Recently, a non-canonical PTEN has been shown to be translated from an upstream initiation codon CUG (leucine) to produce a longer protein called PTEN-Long (PTEN-L). Interestingly, the extended sequence present in PTEN-L contains cell secretion/penetration signal. Role of this non-canonical PTEN-L in diabetic renal tubular injury is not known. We show that high glucose decreases expression of PTEN-L. As a mechanism of its function, we find that reduced PTEN-L activates Akt-2, which phosphorylates and inactivate tuberin and PRAS40, resulting in activation of mTORC1 in tubular cells. Antibacterial agent acriflavine and antiviral agent ATA regulate translation from CUG codon. Acriflavine and ATA, respectively, decreased and increased expression of PTEN-L to altering Akt-2 and mTORC1 activation in the absence of change in expression of canonical PTEN. Consequently, acriflavine and ATA modulated high glucose-induced tubular cell hypertrophy and lamininγ1 expression. Importantly, expression of PTEN-L inhibited high glucose-stimulated Akt/mTORC1 activity to abrogate these processes. Since PTEN-L contains secretion/penetration signals, addition of conditioned medium containing PTEN-L blocked Akt-2/mTORC1 activity. Notably, in renal cortex of diabetic mice, we found reduced PTEN-L concomitant with Akt-2/mTORC1 activation, leading to renal hypertrophy and lamininγ1 expression. These results present first evidence for involvement of PTEN-L in diabetic kidney disease. Competing Interests: Declaration of competing interest The authors do not have any conflict of interest. (Published by Elsevier Inc.) |
| فهرسة مساهمة: | Keywords: Akt-2; Diabetic kidney disease; Matrix protein expansion; PTEN-Long; mTORC1 |
| المشرفين على المادة: | IY9XDZ35W2 (Glucose) EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) EC 3.1.3.67 (PTEN Phosphohydrolase) EC 3.1.3.67 (Pten protein, mouse) |
| تواريخ الأحداث: | Date Created: 20240603 Date Completed: 20240627 Latest Revision: 20240719 |
| رمز التحديث: | 20240719 |
| DOI: | 10.1016/j.yexcr.2024.114116 |
| PMID: | 38830568 |
| قاعدة البيانات: | MEDLINE |
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