# Novel target mechanism (renal nerves) for the beneficial actions of SGLT2 inhibition in congestive heart failure

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2021 · $510,235

## Abstract

Project Summary
One hallmark feature of congestive heart failure (CHF) is sodium and fluid retention and in combination with
neurohumoral activation leads to poor prognosis and high mortality. Sodium-glucose cotransporter 2 (SGLT2) is
localized in the proximal convoluted tubule of the kidney and responsible for 90% of glucose reabsorption. Based
on this fact SGLT2 inhibitors promoting glucose excretion are widely used to treat type 2 diabetic patients. To
date, clinical studies suggest that SGLT2 inhibitors suppress the risk for hospitalization and mortality for heart
failure in type 2 diabetic patients. Further, in non-diabetic patients with CHF, SGLT2 inhibitor prevents worsening
heart failure and mortality. Multiple mechanisms have been proposed to be involved in the beneficial effects of
SGLT2 inhibitors in CHF. Renal sympathetic nerve activation causes sodium and water retention in CHF. Renal
denervation (RDN) has been shown to reduce sodium retention in rats and dogs with CHF. Activation of the
splanchnic sympathetic nerve leads to volume redistribution such as to contribute to cardiopulmonary congestion
in CHF. Our recent evidence in rats with CHF shows that; 1) levels of SGLT2 expression are dramatically
increased in the proximal tubules of the kidney; 2) the activity of SGLT2 for sodium retention is enhanced; 3)
RDN decreases the levels of SGLT2 expression and SGLT2 activity; 4) norepinephrine upregulates SGLT2
expression and trafficking in the renal tubular cells; and 5) RDN attenuates renal levels of inflammatory cytokines
and renal immune cell activation. Based on these data, we will test the hypothesis that elevated sympathetic
activation in CHF enhances sodium reabsorption and fluid retention by modulation of SGLT2 expression,
trafficking and function. Further, enhanced SGLT2 expression potentiates a vicious positive feedback
between renal inflammation and increases in sympathetic activation (both renal and splanchnic nerves)
in CHF. In AIM 1 we will determine if enhanced expression/activation of renal SGLT2 contributes to the sodium
retention in rats with CHF. In AIM 2 we will determine if RDN or selective afferent renal denervation abrogates
the expression/activation of SGLT2, possibly via renal inflammation in rats with CHF. In Aim 3 we will determine
if SGLT2 inhibition reduces efferent/afferent renal and splanchnic sympathetic activation in rats with CHF. These
aims will be addressed in rats with CHF using complementary methodologies ranging from cellular to the whole
animal level, including physiological measurement of sodium balance, volume status, SGLT2 activity,
electrophysiological recording, SGLT2 trafficking using molecular biology techniques. The successful completion
of the proposed studies will provide significant new information and insight into the contribution of SGLT2
inhibition on renal nerve mediated regulation in altered sodium balance in CHF and the therapeutic benefits of
SGLT2 mediated changes in renal nerve...

## Key facts

- **NIH application ID:** 10275320
- **Project number:** 1R01DK129311-01
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** KAUSHIK P PATEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $510,235
- **Award type:** 1
- **Project period:** 2021-08-20 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10275320

## Citation

> US National Institutes of Health, RePORTER application 10275320, Novel target mechanism (renal nerves) for the beneficial actions of SGLT2 inhibition in congestive heart failure (1R01DK129311-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10275320. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*