# Role of homocysteine metabolism, endothelial function and microvascular rarefaction on renal disease severity and progression in ADPKD

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2024 · $593,369

## Abstract

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a devastating systemic disorder
characterized by progressive development and enlargement of bilateral renal cysts leading to renal failure.
Disease severity and progression vary widely among patients. Large phenotypic variability, incomplete
understanding of underlying mechanisms, and lack of satisfactory biomarkers challenge the identification,
implementation and evaluation of potential therapies. In ADPKD, endothelial dysfunction (ED), characterized
by an imbalance between vasodilating (particularly nitric oxide, NO) and vasoconstricting substances, develops
early on and correlates with renal disease severity. We propose that preservation of endothelial function will
ameliorate renal disease severity and progression. Increased homocysteine has been reported in patients with
ADPKD even in those with preserved kidney function. Homocysteine decreases NO availability. However, the
mechanisms underlying increased homocysteine in ADPKD are not known. Elevations in homocysteine reflect
changes in its metabolism, which can be modulated by NADPH oxidase 4 (NOX4). In line with this, we found
upregulation of NOX4, and increased homocysteine, in Pkd1RC/RC mice with early disease. Pharmacologic
reduction of NOX4 restored homocysteine metabolism and reduced cystic burden. Betaine, known to decrease
plasma homocysteine, preserved capillary index, and reduced cystic burden of Pkd1RC/RC mice. Systemic
endothelial function inversely correlated with urine NOX4, plasma homocysteine and renal disease severity by
kidney volume in young normotensive patients with ADPKD. However, whether upregulation of NOX4 redirect
homocysteine metabolism leading to decreased NO availability and ED, and the extent to which ED and
microvascular abnormalities contribute to renal disease severity remain unknown. Similarly, whether markers
of ROS, endothelial function and injury, or levels of homocysteine can predict disease severity and progression
in patients is not known. Our central hypothesis is that early upregulation of NOX4 redirects
homocysteine metabolism leading to its accumulation, which in turn decreases NO availability leading
to ED and microvascular damage, which contributes to ADPKD severity and progression. Three specific
aims will be pursued: Aim 1: will test whether early upregulation in NOX4 redirects homocysteine metabolism
leading to its accumulation in ADPKD. Aim 2: will test whether accumulation of homocysteine decreases NO
availability leading to ED, and whether ED leads to microvascular damage and contributes to disease severity
and progression. Aim 3: will determine the prognostic value of markers of ROS, endothelial function and injury,
and levels of homocysteine to assess disease severity and progression in patients with early ADPKD.
Successful studies will reveal the contribution of microvascular damage to the severity and progression of
ADPKD, and will provide critical biological, preclinical evidence...

## Key facts

- **NIH application ID:** 10813002
- **Project number:** 5R01DK128017-04
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Maria V Irazabal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $593,369
- **Award type:** 5
- **Project period:** 2021-05-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10813002

## Citation

> US National Institutes of Health, RePORTER application 10813002, Role of homocysteine metabolism, endothelial function and microvascular rarefaction on renal disease severity and progression in ADPKD (5R01DK128017-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10813002. Licensed CC0.

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