# New Insights in Mechanisms of Renal Injury

> **NIH VA I01** · SOUTH TEXAS VETERANS HEALTH CARE SYSTEM · 2024 · —

## Abstract

The impact of obesity has been well described in the progression of chronic kidney disease (CKD) with diabetes,
hypertension and even IgA nephropathy, however the basis for how obesity contributes to progressive kidney
disease is unclear. Obesity is often associated with elevated insulin levels and the state of insulin resistance at
the level of muscle and adipose tissue is accepted. The impact of elevated insulin on the kidney is less well
established. Although insulin resistance is a key contributor to podocyte injury, the role of insulin and the insulin
receptor in the proximal tubular cell has not been well studied. In our recent published study we demonstrate
that lack of the insulin receptor in proximal tubular cells of the mouse kidney was renoprotective upon challenge
with a high fat diet. We further demonstrated that insulin down-regulates the cystathione y lyase (CSE) in the
mouse kidney with concomitant inhibition of hydrogen sulfide generation and reduction of AMPK activity. The
reduced hydrogen sulfide may be a key step as addition of hydrogen sulfide restores AMPK activation despite
exposure to insulin in proximal tubular cells. In this new VA Merit proposal, in aim 1 we will examine the role of
AMPK as the major pathway that is downstream of insulin in tubular cells by examining mice that are deficient
in the insulin receptor and AMPK a1 or AMPK a2 catalytic subunits at the tubular level. With our new method of
spatial metabolomics we will determine whether key metabolites are regulated at the tubular level in the kidney
specific proximal tubular insulin receptor knockout (KPTIRKO) mouse. Identification of metabolites in the kidney,
blood and urine will indicate if a circulating biomarker could indicate engagement of the tubular IR and indicate
the status of tubular AMPK activity. In aim 2, we will test the hypothesis that insulin rapidly stimulates
proteasomal degradation of CSE via regulation of Nox4 activity.

## Key facts

- **NIH application ID:** 10721821
- **Project number:** 5I01BX001340-10
- **Recipient organization:** SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
- **Principal Investigator:** Kumar Sharma
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2012-04-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10721821

## Citation

> US National Institutes of Health, RePORTER application 10721821, New Insights in Mechanisms of Renal Injury (5I01BX001340-10). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10721821. Licensed CC0.

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