# Pathogenesis of Diabetic Nephropathy

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $355,500

## Abstract

ABSTRACT
 Diabetic nephropathy (DN) is characterized by disturbances in metabolic & cellular signaling events leading
to increased synthesis of ECM. They include accentuated flux of glucose intermediaries & polyols, aberrations
in fuel sensing molecules, e.g., AMPK; and increased PKC activity, generation of nocuous AGEs, expression of
MAP/ERK kinases and Smad proteins, profibrogenic cytokines & production of reactive oxygen species (ROS).
The latter are regarded as central to the pathogenesis of DN. These signaling events have been studied in
glomerular cells and information for tubular or interstitial cells is limited. Interestingly, tubulointerstitial changes
correlate better with derangement in renal functional parameters; thus there is a legitimate need to define the
biology of DN with respect to “diabetic tubulopathy”. In addition to a multitude of signaling events that affect the
pathology of the glomerulus, a recently discovered glucuronate-xylulose (G-X) pathway, apparently relevant to
diabetic nephropathy that is operative specifically in the tubular compartment, has received very little attention.
Events of G-X pathway are initiated by myo-inositol oxygenase (MIOX), a tubular enzyme that has an increased
expression in DN. During G-X events there are severe perturbations in NADPH:NADP+ & NAD+:NADH ratios,
as a result there is a tremendous degree of "redox imbalance" and "NAD+ deficiency" leading to consequential
adverse tubular homeostasis (JASN 2015, JBC 2016-1). Since MIOX promoter includes carbohydrate, oxidant/
antioxidant, osmotic and sterol response elements a cyclic stimulation of MIOX would be anticipated following
hyperglycemia, lipidemia and chemical oxidant stress (JBC-2011, JBC 2016-2, JASN-2017) along with sustained
up-regulation of MIOX and generation of ROS. Its regulation is also modulated by epigenetic modifications
(AJP 2017). Keeping in perspective the above considerations we wish to explore the mechanisms involved in
the biology of tubulo-interstitium using various genetically modified MIOX mice models. AIM I is to delineate
various epigenetic mechanisms that modulate MIOX expression, using mice models of hyperglycemia and
hyperlipidemia. DNA methylation/demethylation of MIOX promoter, histone methylation/demethylation and
acetylation/decetylation in MIOX-TG and MIOX-KO mice will be investigated and correlated with the extent of
tubulointerstitial injury. AIM II is to delineate mechanisms that accentuate tubulointerstitial injury in MIOX-TG
vs WT or -KO mice during hyperglycemia and AGEs' overload. Perturbations in renal functions, cellular redox,
mitochondrial dynamics will be investigated. Rescue experiments will include cross-breeding Akita with MIOX-/-
mice and various parameters reflecting amelioration of injury appraised. AIM III is to delineate mechanisms
that augment renal injury in MIOX-TG vs WT & KO mice in hyperlipidemia. The events following MIOX over-
expression, i.e., NAD+ deficiency, glutathione depleti...

## Key facts

- **NIH application ID:** 9884754
- **Project number:** 5R01DK060635-18
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** SUSAN E. QUAGGIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $355,500
- **Award type:** 5
- **Project period:** 2002-02-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9884754

## Citation

> US National Institutes of Health, RePORTER application 9884754, Pathogenesis of Diabetic Nephropathy (5R01DK060635-18). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9884754. Licensed CC0.

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