# Vascular Mechanisms of Hypertensive Nephropathy

> **NIH VA I01** · BIRMINGHAM VA MEDICAL CENTER · 2022 · —

## Abstract

Hypertensive nephropathy is a common cause of chronic kidney disease (CKD) and is the
second leading cause of end-stage kidney disease (ESKD). The prevalence of CKD is
significantly higher than the general population and demonstrate progressive loss of kidney
function over time, more attention to the underlying mechanisms of hypertensive nephropathy
are required. Remodeling of the afferent arterioles and accompanying glomerulosclerosis are
hallmarks of human hypertensive nephropathy. Despite extensive investigation, there remain
gaps in understanding why some hypertensive patients develop ESKD, while others do not.
The molecular pathogenesis of the arteriolar remodeling in hypertensive nephropathy would
provide clues to this susceptibility, but the multiple variables that associate with the human
condition limit the ability to provide definitive conclusions. Insight into the molecular basis of
renal microvascular remodeling may therefore be gained through the study of relevant animal
models, in particular the Dahl salt-sensitive (SS) rat, a well-characterized model of hypertensive
nephropathy. Our previous studies, which are described in detail in this application, uncovered
an intrinsic defect in the structural/functional relationship of the renal microvasculature of SS
rats occurring with increases in blood pressure. Preliminary and published studies revealed that
hypertension rapidly upregulated expression of both matrix metalloproteinase-9 (MMP-9) and
Chemokine (C-C motif) Ligand 2 (CCL2), a potent pro-inflammatory chemokine, in kidney
microvasculature of SS rats. We further confirmed that ED-1-positive macrophages collected
around the microvessels of hypertensive SS rats. Our combined findings support the working
hypothesis that hypertension-induced kidney disease in SS rats is initiated by glomerular
injury mediated by microvascular smooth muscle production of a milieu that promotes
inflammation, remodeling, and autoregulatory impairment (Fig. 1). We propose 2 aims:
Aim 1: Determine the novel mechanisms of renal microvascular remodeling and autoregulatory
 dysfunction in SS rats. Hypothesis: MMP-9 mediates afferent arteriolar remodeling and
 impairment of the myogenic response during the development of hypertension.
 1.1 Assess renal afferent arteriolar remodeling and autoregulatory behavior and smooth
 muscle pathobiology of SSMmp9-/- rats.
 1.2 Describe the role of kidney-specific versus systemic expression of MMP-9 in
 microvascular remodeling using a kidney transplant model.
Aim 2: Define the mechanisms of the renal microvascular inflammatory process on
 hypertensive nephropathy in SS rats. Hypothesis: CCL2 is integrally involved in renal
 microvascular remodeling and autoregulatory impairment in hypertensive SS rats.
 2.1 Describe the role of CCL2 in microvascular inflammation and autoregulation in
 SSCcl2-/- rats.
 2.2 Determine the microvascular mechanism of kidney-specific versus systemic
 expression of CCL2 in hypertensive nephropa...

## Key facts

- **NIH application ID:** 10363532
- **Project number:** 1I01BX005640-01A1
- **Recipient organization:** BIRMINGHAM VA MEDICAL CENTER
- **Principal Investigator:** PAUL W. SANDERS
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2022-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10363532

## Citation

> US National Institutes of Health, RePORTER application 10363532, Vascular Mechanisms of Hypertensive Nephropathy (1I01BX005640-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10363532. Licensed CC0.

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