# Mechanisms of renal immune cell infiltration in salt-sensitive hypertension

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $574,543

## Abstract

PROJECT SUMMARY
Salt-sensitive hypertension is a significant health problem; there is a need to understand the underlying
mechanisms to enable more effective treatments. The proposed studies are based on a strong scientific
foundation with experiments performed in our laboratories in Dahl salt-sensitive (SS) rats demonstrating that
both renal H2O2 production and inflammation play key roles in the initiation and progression of salt-sensitive
hypertension, but the connection between these two has thus far not been elucidated. Based on prior work and
exciting preliminary data, we hypothesize that renal inflammation in SS rats fed high salt is driven by an initial
rise of arterial pressure with elevated Nox4-derived H2O2 production. This, in turn, results in leukocyte adhesion
and infiltration into the kidney via activation of matrix metalloproteinase (MMP)-2 and -9 and the NLRP3
inflammasome. The infiltrated immune cells produce additional MMP-2 and H2O2 (and superoxide [O2-]) from
Nox2 which facilitates the transition from a pre-hypertensive state to accelerated malignant hypertension and
end-stage renal injury. Several unique methodologies enable us to address this overall hypothesis. First, we
have developed an SS rat containing a null mutation in Nox4 (SSNox4-/-), a unique model of reduced H2O2
production with reduced salt-sensitive hypertension. Second, we have also developed novel SS rat strains with
null mutations in MMP-2, MMP-9, and NLRP3 (SSMMP2-/-, SSMMP9-/-, and SSNLRP3-/-) enabling us to determine
their involvement in salt-sensitive hypertension. Third, a custom-designed servo-control system which is
unique to our laboratory enables the precise chronic control of renal perfusion pressure (RPP) to the left kidney
of SS rats thereby allowing us to separate the effects of renal H2O2 production from those of differing RPPs.
Moreover, given the profound effect of RPP on renal immune cell infiltration, this system enables us to perform
pressure-matching studies to isolate the effects of genetic mutation of NLRP3, MMP-2 and MMP-9 on renal
inflammation from the confounding effects of different RPP in the models. Finally, sophisticated bone marrow
transfer studies, which utilize our genetically modified SS strains (SSp67phox-/- and SSMMP2-/-), will enable us to
determine the relative contributions of parenchymal- and hematopoietic-derived H2O2/reactive oxygen species
and MMP-2 to salt-sensitive hypertension and renal injury. This proposal has three Specific Aims: 1) will test
the hypothesis that an initial rise of BP accompanied by elevated Nox4-derived H2O2 mediates immune cell
infiltration into the kidney of hypertensive rats fed high salt; 2) will test the hypothesis that upregulation of
MMP-2, MMP-9 and the NLRP3 inflammasome mediates renal immune cell infiltration in SS rats and
participates in the progression of salt-induced hypertension; and 3) will test the hypothesis that T-cells that
infiltrate into the kidney enhance H2O2 production v...

## Key facts

- **NIH application ID:** 9873068
- **Project number:** 5R01HL137748-03
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Allen W Cowley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $574,543
- **Award type:** 5
- **Project period:** 2018-05-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9873068

## Citation

> US National Institutes of Health, RePORTER application 9873068, Mechanisms of renal immune cell infiltration in salt-sensitive hypertension (5R01HL137748-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9873068. Licensed CC0.

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