NIH grant: Targeting CtBP2 to Modulate Redox-Transcriptional Programs and Prevent Renal Tubular Cell Death in AKI (1R01DK140315-01A1)

retained text

NIH grant 1R01DK140315-01A1: Targeting CtBP2 to Modulate Redox-Transcriptional Programs and Prevent Renal Tubular Cell Death in AKI
Institute: {'code': 'DK', 'abbreviation': 'NIDDK', 'name': 'National Institute of Diabetes and Digestive and Kidney Diseases', 'admin_org_id': '12500020', 'admin_funding_url': ''}. PI: Jiyoung  Kim. Award: $1527305.
Start: 2026-08-21T00:00:00.
PROJECT SUMMARY
Acute kidney injury (AKI) affects over 13 million patients annually and remains without effective treatments, with
significant impact on patient outcomes and healthcare burden. Identification of causal drivers of injury that are
also druggable remains a critical unmet need. During AKI, proximal tubular cells undergo metabolic collapse
including ATP and NAD⁺ depletion and mitochondrial dysfunction, which triggers maladaptive transcriptional
programs and renal epithelial cell death. The upstream regulators that couple metabolic stress to pathogenic
transcriptional states remain undefined. This proposal identifies C-terminal Binding Protein 2 (CtBP2), a redox-
sensitive, NAD⁺/NADH-dependent transcriptional corepressor, as a previously unrecognized and mechanistically
tractable driver of tubular injury. CtBP2 is strongly induced in injured proximal tubules in both human and murine
AKI. Its genetic deletion or pharmacologic inhibition restores metabolic gene expression, preserves tubular
function, and improves renal outcomes in murine AKI models. We hypothesize that CtBP2 senses redox
imbalance during AKI and drives tubular injury by repressing key genes involved in NAD⁺ biosynthesis and
mitochondrial metabolism. We propose to test this hypothesis in two aims: (1) define the functional impact of
genetic and pharmacological CtBP2 inhibition in murine models of ischemic, nephrotoxic, and rhabdomyolysis-
associated AKI, as well as in an ischemic porcine model; and (2) identify upstream regulators and downstream
targets of CtBP2 using RNA sequencing, metabolomics, ChIP-sequencing and promoter-reporter assays. The
significance of this work lies in defining a core injury pathway that links metabolic dysfunction to transcriptional
repression and establishes CtBP2 as a novel therapeutic target in AKI. The innovation lies in targeting a redox-
sensitive transcriptional regulator not previously studied in kidney disease, combined with advanced genetic
models, molecular profiling approaches, and translational large-animal studies. This work is expected to
establish CtBP2 as a central driver of metabolic injury in AKI and provide proof-of-concept for the future clinical
development of CtBP2-targeted therapies.

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