# BLRD Research Career Scientist Award Application

> **NIH VA IK6** · SOUTH TEXAS VETERANS HEALTH CARE SYSTEM · 2024 · —

## Abstract

Diabetes is the number one cause of end stage kidney disease and accounts for approximately 47% of
cases in the US. More than 34 million Americans have diabetes. It is prevalent in the people aged 18 years and
older. The demographic of Veteran population falls in this age group. In Veterans aged 65 years and older,
approximately 27% are afflicted with diabetes. A recent study demonstrated that diabetic patients with kidney
disease had 87% higher risk of cardiovascular mortality. One in three patients with diabetes develop diabetic
nephropathy (DN). Early pathologic changes in DN involve renal, especially glomerular hypertrophy and
expansion of matrix proteins. The focus of our research is to investigate the signal transduction mechanisms that
lead to the progression of DN. To test our concepts, we use both renal glomerular mesangial and proximal
tubular epithelial (PTE) cells in culture and, mouse and rat models of diabetes exhibiting kidney pathologies. In
kidney, high levels of transforming growth factor-b (TGFb) mediate many pathologic effects of hyperglycemia.
Therefore, along with the effects of high glucose, we investigate the signaling mechanisms of TGFb in mesangial
and PTE cells. We were the first to discover that high glucose decreases the expression of the tumor suppressor
protein PTEN (phosphatase and tensin homolog deleted in chromosome 10) in these cells and in the renal
tissues of diabetic mice and rats. We identified that this effect of high glucose is mediated by TGFb. In
investigating the mechanisms, we for the first time reported that multiple microRNAs such as miR-21, miR-26
and miR-214 that are significantly increased in the diabetic kidneys regulate the hyperglycemia- and TGFb-
induced inhibition of PTEN. In fact, we showed that this inhibition of PTEN expression resulted in sustained
activation of Akt kinase that led to activation of mTORC1 (mechanistic target of rapamycin complex 1). mTORC1
contributes to mesangial and PTE cell hypertrophy, and expression of matrix proteins fibronectin and collagen I
a2 causing renal hypertrophy and fibrosis in DN. Indeed, we showed that rapamycin ameliorated complications
of DN including albuminuria in type 1 and type 2 diabetic mice. Since increased expression of above-mentioned
microRNAs contribute to PTEN inhibition/Akt kinase-mediated mTOR activation, our studies opened the door to
the novel application of anti-miR therapy for DN. Rapamycin-mediated complete inhibition of mTORC1 causes
deleterious clinical outcome. Proximal tubular loss of mTORC1 in mice showed progressive renal fibrosis.
Therefore, more recently we have focused on a novel protein, called deptor, which is a component of mTOR and
is a negative regulator of both mTORC1 and mTORC2 activities. For the first time, we showed that the renal
expression of deptor was significantly reduced in humans with diabetes and in diabetic rodents. This reduction
contributed to enhanced mTOR activity. We also found that both high glucose ...

## Key facts

- **NIH application ID:** 10726563
- **Project number:** 5IK6BX005795-03
- **Recipient organization:** SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
- **Principal Investigator:** GOUTAM GHOSH CHOUDHURY
- **Activity code:** IK6 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2021-10-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10726563

## Citation

> US National Institutes of Health, RePORTER application 10726563, BLRD Research Career Scientist Award Application (5IK6BX005795-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10726563. Licensed CC0.

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