# Mechanisms of Tubular Atrophy

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $633,502

## Abstract

Over 30M people in the U.S. suffer from diabetes; one-third have CKD and almost half of incident ESRD is
due to diabetic kidney disease (DKD). Albuminuria and decreased GFR reflect glomerular dysfunction, and are
risks for DKD progression. However, tubular atrophy is superior to glomerular pathology as a predictor of DKD
progression. The mechanisms for loss of tubular epithelial cells have not been established.
 Non-esterified fatty acids (NEFA) circulate bound to albumin, or as triglycerides. Neither is filtered due to
their size. Low concentrations of filtered NEFA are reabsorbed by apical scavenger transporters in the proximal
tubule. This segment normally uses NEFA as metabolic substrates that are taken up across the basolateral
membrane. In DKD, injured glomeruli permit filtration of albumin-bound NEFA in large quantities, which are
then reabsorbed by apical proximal tubule transporters, causing accumulation of NEFA, long-chain acyl-CoAs,
and apoptosis. Apical NEFA uptake is mediated primarily by fatty acid transport protein-2 (FATP2), and at
NEFA concentrations that mimic DKD in vitro, is cytotoxic. Basolateral NEFA uptake is FATP2-independent
and not cytotoxic.
 We showed that global FATP2 deletion in genetic and inducible mouse models of DKD improves GFR,
tubular atrophy and plasma glucose, but the mechanisms are not understood. First, FATP2 deletion does not
completely block AP proximal tubule NEFA uptake. Second, how FATP2 deletion account for the enhanced
synthesis and decreased degradation of NEFA associated with DKD, has not been reconciled.
 In DKD proximal tubules accumulate lipid droplets (LD), which store excess NEFA to prevent lipotoxicity.
Perilipin (Plin) proteins facilitate LD assembly and maintenance. Plin5 augments LD docking with mitochondria,
thereby enhancing autophagy, reducing ER stress and apoptosis, and shifts metabolism from -oxidation to
lipid storage and glucose utilization. Our data show that proximal tubule Plin5 expression is blunted in DKD,
and increased with FATP2 deletion. Plin5 overexpression inhibited, and Plin5 loss of function exacerbated
lipoapoptosis. These data suggest that the beneficial effect of FATP2 deletion is partly due to enhanced
expression of Plin5. We also propose that Plin5 mediates metabolic reprogramming from -oxidation to
glycolysis and decreased gluconeogenesis, which would mediate the hypoglycemic effects of FATP2 deletion.
 Hypothesis: In DKD-associated glomerular injury, constitutive basolateral NEFA transport, combined with
apical FATP2-regulated proximal tubule NEFA uptake leads to lipotoxicity, tubular atrophy and progressive
DKD. Tubular atrophy can be circumvented by proximal tubule FATP2 deletion or enhanced Plin5-dependent
lipid droplet expansion. The hypothesis will be pursued with the following specific aims: 1. To determine
whether proximal tubule FATP2 mediates lipotoxicity and DKD progression. 2. To determine the role of Plin5 in
proximal tubule metabolism and DKD. 3. To...

## Key facts

- **NIH application ID:** 10873360
- **Project number:** 5R01DK067528-15
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** JEFFREY R SCHELLING
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $633,502
- **Award type:** 5
- **Project period:** 2005-08-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873360

## Citation

> US National Institutes of Health, RePORTER application 10873360, Mechanisms of Tubular Atrophy (5R01DK067528-15). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10873360. Licensed CC0.

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