# Ketosis as a therapy for polycystic kidney disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA SANTA BARBARA · 2021 · $393,496

## Abstract

Project Summary/Abstract
We have previously shown that a mild reduction in food intake strongly inhibits progression of polycystic kidney
disease (PKD) in an orthologous mouse model but we did not understand the mechanism. Now, we discovered
that the metabolic state of ketosis is important, not caloric restriction per se. Dietary interventions leading to
ketosis profoundly inhibit - and even reverse - PKD progression in orthologous and non-ortholgous mouse, rat
and feline models of PKD. Remarkably, treatment with the ketone β-hydroxybutyrate (BHB) alone is almost
100% effective in preventing PKD progression. Preliminary results suggest that BHB acts on PKD kidneys via
its receptor GPR109a, a GPCR that suppresses cAMP signaling. Our results suggest that cyst cells in PKD are
metabolically in?exible, depend on glucose and are unable to shift to utilizing fatty acids and ketone bodies.
The main thrust of this proposal is to generate compelling results to justify clinical trials to investigate the
ef?cacy of dietary interventions and/or BHB supplementation in ADPKD, and to inform the design of such trials.
The main signi?cance of this proposal is the enormous potential for clinical translation. Dietary interventions to
induce ketosis are well-established. Because dietary interventions frequently fail in clinical practice due to poor
adherence, our ?nding that BHB (an FDA-classi?ed dietary supplement) has a dominant bene?cial effect could
rapidly lead to a highly feasible therapy. To achieve our goals, we will treat rodent and feline models of PKD,
with dietary interventions to induce ketosis (time-restricted feeding or ketogenic diets) or mimic ketosis by
supplementation with BHB. Ef?cacy on parameters of PKD progression and effects on molecular mechanisms
will be assessed. To determine whether BHB acts via GPR109a, we have crossed Gpr109a-/- mice with fast-
and slowly-progressing Pkd1 mouse models. We will test whether Gpr109a knock-out affects disease
progression and prevents the ef?cacy of ketogenic dietary intervention or BHB. Successful completion of the
proposed work could lead to a disruptive change in ADPKD therapy by utilizing dietary interventions and/or
dietary supplements without the need for pharmacological intervention.

## Key facts

- **NIH application ID:** 10127636
- **Project number:** 5R01DK124895-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA SANTA BARBARA
- **Principal Investigator:** Thomas Weimbs
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $393,496
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10127636

## Citation

> US National Institutes of Health, RePORTER application 10127636, Ketosis as a therapy for polycystic kidney disease (5R01DK124895-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10127636. Licensed CC0.

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