# Mechanisms of Renal Cell Injury

> **NIH VA I01** · SOUTH TEXAS VETERANS HEALTH CARE SYSTEM · 2022 · —

## Abstract

Pathologic manifestations of diabetic nephropathy (DN) include glomerular and tubular hypertrophy and
matrix protein fibronectin expression. These changes occur concomitant with increased expression of TGFb
(transforming growth factor-b) that contributes to the pathogenesis of human and experimental DN. We
interrogate the molecular signaling events by which high glucose and TGFb drive the pathologies and provide
new potential therapeutic strategies for complications of DN. We have reported that Akt kinase/mTORC1
(mechanistic target of rapamycin complex 1) axis contributes to renal hypertrophy and fibronectin expression in
mesangial and proximal tubular epithelial (PTE) cells, and in kidneys of type 1 and type 2 diabetic mice.
Recently, a novel longer translational variant of PTEN (phosphatase and tensin homolog deleted in
chromosome 10), PTEN-Long, a negative regulator of Akt kinase, has been identified as a secretory and
membrane permeable protein. Our preliminary data show markedly reduced levels of PTEN-Long along with
increased Akt kinase activity in the kidney cortex of type 1 and type 2 diabetic mice and in high glucose- or
TGFb-treated mesangial and PTE cells. Moreover, we show that high glucose and TGFb activate PDGFRb
(platelet-derived growth factor-b). We find PDGFRb as a substrate for PTEN-Long; thus downregulation of
PTEN-Long results in PDGFRb activation by high glucose and TGFb. Furthermore, in the kidney and in
mesangial and PTE cells, we identify Akt-2 as the predominant isotype of Akt kinase that acts downstream of
PTEN-Long/PDGFRb. Also, Akt-2 is activated in kidneys of type 1 and type 2 diabetic mice kidneys. We plan
to exploit the intrinsic protective function of PTEN-long during the progression of DN. In this proposal, using
cultured mesangial and PTE cells and renal tissues from diabetic OVE26 and db/db mice, we will test the
hypothesis that hyperglycemia/TGFb-induced inappropriate downregulation of PTEN-Long results in
PDGFRb/Akt-2 activation that contributes to renal hypertrophy and matrix expansion in diabetic kidney
disease. Probing the novel negative regulatory function of PTEN-Long, we will use it as a therapeutic agent for
DN. In the first specific aim, we will determine the role of PTEN-Long in hypertrophy and, fibronectin and PAI-1
(plasminogen-activator inhibitor-1) expression. In the second aim, how PTEN-Long forces activation of
PDGFRb to regulate mesangial and PTE cell hypertrophy, and matrix protein expression will be investigated.
In specific aim 3, we will study the contribution of Akt-2 isotype to hypertrophy and fibronectin/PAI-1 expression
in response to high glucose and TGFb in mesangial and PTE cells and in diabetic mice kidneys. To address
these aims, techniques including immunoblotting, immunoprecipitation, morphometry, immunohistochemistry,
transfection of expression vectors and siRNAs, administration of recombinant therapeutic protein and small
molecule compound will be employed. Our study will estab...

## Key facts

- **NIH application ID:** 10293566
- **Project number:** 5I01BX000926-10
- **Recipient organization:** SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
- **Principal Investigator:** GOUTAM GHOSH CHOUDHURY
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2011-07-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10293566

## Citation

> US National Institutes of Health, RePORTER application 10293566, Mechanisms of Renal Cell Injury (5I01BX000926-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10293566. Licensed CC0.

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