# The role of angiotensin-converting enzyme in renal inflammation, kidney injury and sodium retention during diabetic nephropathy

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2020 · $425,000

## Abstract

ABSTRACT
Diabetic nephropathy is a serious microvascular complication of diabetes and the main cause of end-
stage renal disease. Several studies have demonstrated a critical role of inflammation in the
pathogenesis of diabetic kidney disease. This inflammatory response injures the renal parenchyma and
promotes a defective sodium handling that, ultimately, predispose to hypertension. Although strong
evidence supports these observations, the molecular mechanisms behind the increased sodium retention
of the diabetic nephron remain unknown. Research demonstrates that angiotensin-converting enzyme
(ACE) is a major player in the progression of renal inflammation. Although most effects of ACE have
been classically related to angiotensin II synthesis, recent studies highlight a role of ACE in inflammation
and immune response through mechanisms that are independent of angiotensin II production. Indeed,
ACE has two catalytically independent domains, known as the N- and C-domains, that can process a
wide diversity of substrates besides angiotensin I. Preliminary data show that renal tubular epithelial cells
produce interleukin-1β (IL-1β) in response to high glucose through a mechanism that requires a
functional ACE N-domain and is independent of angiotensin II synthesis. This cytokine regulates the
activity of renal sodium transporters. Also, in vivo studies show that diabetic mice lacking a functional
ACE N-domain display lower levels of renal IL-1β and have improved sodium handling compared to wild-
type diabetic mice. Based on these data, I hypothesize that, during diabetes, ACE regulates the release
of IL-1β from renal tubular epithelial cells through a mechanism that is independent from angiotensin II
generation. IL-1β further contributes to the inflammatory response and the impaired sodium handling
associated with diabetic nephropathy. To explore this, I propose three specific aims: 1) To investigate the
specific contribution of the ACE C- and N-domains to the production of IL-1β by renal epithelial cells and
determine how this cytokine regulates renal sodium transporter activity in vitro. 2) To determine the
mechanism by which the ACE C- and N-domains contribute to the development of kidney injury and
impaired sodium handling associated with diabetic nephropathy in vivo. 3) To study the source, the
cellular target and the role of IL-1β in kidney injury and impaired sodium handling associated with
diabetic nephropathy. In conclusion, this proposal suggests a novel biochemical communication between
different portions of the nephron where cytokines produced by epithelial cells can modify the sodium
avidity along the nephron. These studies might lead to new therapeutic approaches to treat diabetic
nephropathy and prevent the development of serious clinical conditions such as end-stage renal disease.

## Key facts

- **NIH application ID:** 9952415
- **Project number:** 5R01HL142672-03
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Jorge Fernando Giani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $425,000
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9952415

## Citation

> US National Institutes of Health, RePORTER application 9952415, The role of angiotensin-converting enzyme in renal inflammation, kidney injury and sodium retention during diabetic nephropathy (5R01HL142672-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9952415. Licensed CC0.

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