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Abstract: FR-PO344

PTEN-Long Suppresses Proximal Tubular Epithelial Cell (PTEC) Injury in Diabetic Nephropathy (DN)

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic


  • Das, Falguni, UT Health VA Hospital, San Antonio, San Antonio, Texas, United States
  • Ghosh-choudhury, Nandini, UT Health, San Antonio, Texas, United States
  • Kasinath, Balakuntalam S., UT Health, San Antonio, Texas, United States
  • Ghosh-Choudhury, Goutam, UT Health VA Hospital, San Antonio, San Antonio, Texas, United States

From the same mRNA, a translational variant with CUG codon (Leu)-initiated PTEN with a 173 amino acids long N-terminus (PTEN-L) compared to canonical PTEN has recently been identified. Both PTENs provide a checkpoint against tumorigenesis. We investigated the hypothesis that PTEN-L acts as a driver of tubular injury in the progression of DN.


Human PTECs, OVE26 and db/db mice, specific antibodies, immunoblotting, PTEN-L-targeting drugs, measurement of hypertrophy and plasmid expression vector were employed.


25 mM glucose (HG) time-dependently decreased the expression of PTEN-L. PTECs predominantly express Akt-2 isoform. Concomitant with decreased PTEN-L, HG increased phosphorylation of Akt-2 and its substrate GSK3β. The anti-bacterial chromophore acriflavine (ACR) inhibits initiation from CUG codon. ACR inhibited the expression of PTEN-L. In contrast, aurin tricarboxylic acid (ATA), a potent anti-viral agent, increases translation from CUG codon and increased the expression of PTEN-L. Consequently, ACR increased Akt-2 phosphorylation/activation (p-GSK3β) similar to HG while ATA inhibited these events. These drugs had no effect on canonical PTEN expression. As Akt-2 regulates mTORC1 via phosphorylation/inactivation of tuberin and PRAS40, we determined the effect of these drugs. ACR increased their inactivating phosphorylation, resulting in activation of mTORC1, as judged by phosphorylation of S6 kinase, eEF2 kinase and dephosphorylation of eEF2; these effects were similar to HG. ATA blocked these effects induced by HG. ACR induced PTEC hypertrophy and fibronectin and PAI-1 expression similar to HG while ATA inhibited these HG-induced phenomena. To confirm the results with ATA, we used a plasmid vector expressing PTEN-L. PTEN-L suppressed HG-induced phosphorylation of Akt-2/GSK3b, resulting in inhibition of mTORC1 activity and blocked HG-induced PTEC hypertrophy and, expression of fibronectin and PAI-1. In addressing the in vivo relevance of our results, in the renal cortex of OVE26 and db/db mice models of type 1 and type 2 diabetes, we found decreased expression of PTEN-L concomitant with increased phosphorylation of Akt-2/GSK3b, mTORC1 activation, and fibronectin and PAI-1 expression.


We conclude that PTEN-L protects against PTEC injury in DN.


  • Veterans Affairs Support