# Protein Nutrition in Experimental Uremia

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $356,625

## Abstract

Project Summary/Abstract
For years, we have been intrigued by our observation that uremia stimulates protein degradation but it also
suppresses protein synthesis, leading to protein-energy wasting. Specifically, we have documented that protein
degradation is induced by activation of caspase-3 and the ubiquitin-proteasome system (UPS) but the
mechanism underlying uremia-stimulated impairment in protein synthesis is unknown. Our long term goal is to
identify how chronic kidney disease (CKD) activates key regulatory pathways that cause protein-energy
wasting because this is the first step to developing therapeutic interventions to improve the morbidity and
mortality in patients with CKD. In this application, we plan to identify how CKD impairs protein synthesis. For
this task, we have found that CKD stimulates the expression of a novel protein, nucleolar protein 66 (NO66).
NO66 expression represses ribosomal DNA (rDNA) transcription. NO66 contains a JmjC domain with histone
demethylase activity. Since rDNA transcription determines the rate of protein synthesis, we propose that
uremia impairs muscle protein synthesis via an NO66-dependent, epigenetic mechanism, Our Preliminary
Results support this hypothesis: 1) we show that CKD stimulates NO66 expression in muscle biopsies of
patients or mice. 2) We have created whole body knockout of NO66 in mice (NO66-/-) and determined that it
accelerates muscle growth (NO66-/- mice experienced a 20-30% increase in muscle vs. changes in control
mice). In addition, NO66-/- mice suppress CKD-induced protein-energy wasting. 3) We have created mice with
muscle-specific KO of NO66 (NO66mko) and we found that NO66mko stimulates protein stores. 4) We find that
NO66 forms a repressive complex with two histone-modifying proteins, retinoblastoma binding protein 4
(RBBP4) plus histone deacetylase 2 (HDAC2). The repressive complex potentially associates with rDNA and
represses its transcription, resulting in decreased protein synthesis. 5) Our RNA-seq analysis using soleus
muscle identified increased ribosomal bigenesis signaling pathway in muscles lacking NO66. There also is a
significant increase in both rRNA and the ribosomal translational capacity in muscle of NO66-/- mice vs. results
from NO66flox/flox mice. Based on these novel findings, we hypothesize that a NO66-mediated epigenetic
pathway is the answer to the long standing query: how does uremia suppress protein synthesis? We propose
three Specific Aims to test our hypotheses: 1) To determine the mechanism by which CKD stimulates NO66
expression contributing to protein-energy wasting. 2) To determine whether the NO66 complex binds to rDNA
and represses rDNA transcription via a demethylase-dependent mechanism.3) To determine if the absence of
NO66 in muscle will increase protein synthesis and prevent uremia-induced protein-energy wasting. Our
results could uncover strategies for improving protein synthesis despite the presence of CKD or possibly, other
catabolic cond...

## Key facts

- **NIH application ID:** 9891046
- **Project number:** 5R01DK037175-34
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Zhaoyong Hu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $356,625
- **Award type:** 5
- **Project period:** 2018-05-02 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891046

## Citation

> US National Institutes of Health, RePORTER application 9891046, Protein Nutrition in Experimental Uremia (5R01DK037175-34). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9891046. Licensed CC0.

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