# Protective factors in diabetic kidney disease in patients with type 1 diabetes

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2022 · $556,916

## Abstract

Scientific Abstract: Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. While DKD
injury factors are extensively studied, protective factors remain poorly defined and present a critical knowledge
gap. Recently we and others described the existence of potential protective and healing mechanisms in DKD.
These concepts warrant further investigation and have the potential to greatly improve outcomes. Papers from
our and other laboratories confirm that after multiple passages cultured skin fibroblasts (SF) behaviors differ
between patients with versus without DKD. Consistent with protective mechanisms, our earlier gene
expression studies showed that individuals protected from DKD had some SF behaviors that differ both from
patients with DKD and from normal controls, suggesting the protected group had unique cellular behaviors
associated with very slow development of DKD lesions. Our recent gene expression studies (hi-seq) in SF grown
in high glucose (HG) uncovered that pathways related to DNA replication and repair, protein repair, and cell cycle
were markedly overexpressed in patients with type 1 diabetes (T1D) without DKD as compared to T1D patients
with DKD and non-diabetic controls. These pathways were also differently expressed in SF of monozygotic twins
discordant for T1D. Thus, upregulation of these pathways is posited as protective of DKD and epigenetically
regulated. Hyperglycemia induces DNA damage, thus activating DNA repair pathways [primarily the base
excision repair (BER) pathway] in order to restore DNA integrity and prevent cellular dysfunction. Indeed, the
BER pathway was markedly up-regulated in T1D patients without DKD (p=5.14e-5) as compared to patients with
DKD and controls. Our preliminary data indicate that BER pathway is also upregulated in proximal tubular
epithelial cells (PTEC). We will test whether these pathway differences are associated with functional differences
in SF and PTEC cultured from research skin and kidney biopsies in T1D volunteers. Our Specific Aims are to
determine 1) changes in BER protein levels, DNA damage and repair capacity in SF in response to in vitro HG
and their relationship to DKD risk, 2) changes in BER protein levels, DNA damage, repair capacity and response
to a therapeutic agent in PTEC cultured in HG and their relationship to DKD risk, 3) urinary levels of DNA damage
products in relation to DKD risk, and 4) epigenetic mechanisms associated with gene expression in key
differentially expressed BER pathway genes. We hypothesize that, although both T1D patients with and without
DKD may have increased BER pathway activity compared to controls, this activity will be much greater in the
patients protected from DKD, and that our robust SF findings will be recapitulated in PTEC. Given the depth of
our basic science strengths in the relevant areas, the unique research materials, the innovative technical
capabilities of our superb investigative team, and our proven collaborati...

## Key facts

- **NIH application ID:** 10323271
- **Project number:** 5R01DK121019-03
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Maria Luiza A Caramori
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $556,916
- **Award type:** 5
- **Project period:** 2020-03-05 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10323271

## Citation

> US National Institutes of Health, RePORTER application 10323271, Protective factors in diabetic kidney disease in patients with type 1 diabetes (5R01DK121019-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10323271. Licensed CC0.

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