# The role of the M1 macrophage response in the progression of chronic kidney disease

> **NIH VA I01** · DURHAM VA MEDICAL CENTER · 2020 · —

## Abstract

Macrophages can have profound effects on the progression of chronic kidney disease (CKD) by shaping the
innate immune response. For example, pro-inflammatory M1 macrophages secrete tumor necrosis factor-
(TNF) and Interleukin-1 (IL-1), both of which can promulgate kidney injury and fibrosis. Through activation of
type 1 angiotensin (AT1) receptors in the kidney, the renin angiotensin system (RAS) similarly plays a key role
in progressive kidney damage culminating in renal fibrosis. However, in contrast to the pathogenic actions of
renal AT1 receptors, our recent studies have shown that stimulation of AT1 receptors directly on macrophages
suppresses their generation of M1 cytokines and thereby protects the kidney from progressive fibrosis. We
further find that activating the AT1 receptor on macrophages enhances their expression of the transcription
factor Krüppel like factor 4 (KLF4). In other disease models, KLF4 blunts the M1 polarization of
macrophages, limiting their secretion of TNF, and we find that global TNF-deficiency ameliorates
hypertensive CKD induced by RAS activation. We therefore hypothesize that AT1 receptor activation on
macrophages attenuates RAS-dependent kidney damage and fibrosis by enhancing KLF4-mediated
suppression of TNF. To test this, we will first determine the role of macrophage KLF4 in kidney disease,
assessing renal damage and fibrosis in mice lacking KLF4 only in macrophages and wild-type controls
subjected to the chronic angiotensin II infusion (HTN) and unilateral ureteral obstruction (UUO) models of
kidney injury and fibrosis. We predict that KLF4-deficiency in macrophages will exacerbate RAS-dependent
CKD by exaggerating their generation of TNF. Therefore, as a next step we will assess the contribution of the
enhanced TNF production in macrophages to RAS-dependent CKD by subjecting mice with macrophage-
specific TNF deletion (TNF MKO) to our HTN and UUO models of RAS activation. Lastly, our hypothesis
predicts that during treatment with a global AT1 receptor blocker (ARB), TNF induction accruing from AT1
receptor blockade on macrophages will diminish the renal protection afforded by blockade of renal AT1
receptors. To test this, we will compare HTN- and UUO-induced renal injury in TNF MKO and wild-type mice
treated with an ARB and will determine if mice with macrophage-specific deletion of both TNF and the AT1
receptor have less kidney injury than those lacking the macrophage AT1 receptor alone. In the near term,
these studies should guide strategies to use cytokine receptor blockade in conjunction with ARBs during
progressive CKD. Over the longer term, distinguishing the contribution of AT1 receptors in the kidney to
promote CKD progression from the protective effects of AT1 receptors on macrophages to mitigate M1-
dependent tissue damage should facilitate the design of improved treatments for CKD.

## Key facts

- **NIH application ID:** 9814674
- **Project number:** 5I01BX000893-08
- **Recipient organization:** DURHAM VA MEDICAL CENTER
- **Principal Investigator:** Steven D Crowley
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2012-01-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9814674

## Citation

> US National Institutes of Health, RePORTER application 9814674, The role of the M1 macrophage response in the progression of chronic kidney disease (5I01BX000893-08). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9814674. Licensed CC0.

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