# Animal Models for Studying the Genetics of Hypertension

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $735,815

## Abstract

Diabetes mellitus, an increasingly common disease, can cause diabetic nephropathy (DN) and diabetic
cardiomyopathy (DCM), leading often to the need for dialysis and kidney transplantation, and to heart failure or
stroke. Current knowledge of genes associated with an increased risk for diabetic complications is very
limited. Diabetic complications at present are treated by intense glycemic control and management of end
organ damages; specific treatment is lacking. Developing and studying mouse models of diabetes that
recapitulate the complications seen in the later stages of human diabetes is a powerful approach to enhance
our knowledge of genetic risk factors and can contribute to developing preventive and therapeutic measures.
During the past grant period we modified several genes expected to affect blood pressure or cardiac/kidney
function to obtain a low expressing form of the chosen gene (L) that could be switched to high (H) globally or in
a tissue-specific or time-controlled manner with a tamoxifen-inducible Cre. The most serious effects on
cardiac/renal function were observed in male mice that were type1diabetic because they had the Akita
mutation in the Ins2 gene and had high expression (H/H) of Elmo1, the gene coding for Engulfment and cell
motility protein 1. [Associations of SNPs in the ELMO1 gene with DN have been demonstrated in multiple
populations.] Accordingly, Specific Aim (i) will focus on increasing our knowledge of the mechanisms that
underlie the harmful effects of high Elmo1 expression on DCM and DN, and Specific Aim (ii) will determine
the cell types in which Elmo1 high expression acts in enhancing these diabetic complications.
Diabetes increases production of the superoxide anion (O2.), a free radical that generates reactive oxygen
species (ROS), and the diabetic Elmo1 H/H and Elmo1 H/+ mice have high levels of plasma TBARS (a
measure of ROS). Vitamin B12, a normal body constituent generally regarded as safe by the FDA, is a
superoxide dismutase mimic, but its potential for inactivating ROS is normally limited because absorption of
B12 from the diet is controlled by the small amount of intrinsic factor secreted by the gastric mucosa. However,
our preliminary work shows that feeding B12 at high doses enables absorption of the vitamin by an intrinsic-
factor-independent pathway that overcomes this limitation; plasma TBARS are normalized, and DCM is no
longer seen in young adult Elmo1 H/H diabetic male mice treated with B12. Accordingly, Specific Aim (iii) will
optimize the dose of B12 needed to prevent/correct the DCM and DN in Elmo1 H/H diabetic males, compare it
with another SOD mimetic (EUK-34) and with tempol, a free radical scavenger, and will determine whether the
vitamin affects resistance to microorganisms. Specific Aim (iv) will determine whether B12 has the same
benefits in Elmo1 H/H: Ins2 Akita/+ females, and in db/db Elmo1 H/H mice expected to develop type2 DM.

## Key facts

- **NIH application ID:** 9900037
- **Project number:** 5R01HL049277-29
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** NOBUYO MAEDA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $735,815
- **Award type:** 5
- **Project period:** 1992-09-30 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9900037

## Citation

> US National Institutes of Health, RePORTER application 9900037, Animal Models for Studying the Genetics of Hypertension (5R01HL049277-29). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9900037. Licensed CC0.

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