Ketogenic Diet Promotes Renal Fibrosis in Healthy Tissue via Wnt8b and Junb, While Protecting Against Injury-Induced...

The ketogenic diet (KD) is widely used in disease management and healthy populations, but its long-term physiological safety remains unclear. While KD protects against kidney injury in models, its effects on healthy renal tissue are poorly understood.

Two-sample Mendelian randomization (MR) analyzed causality between serum 3-hydroxybutyrate (BHB) and renal injury. Mice underwent 3-month KD, short-term BHB gavage, or time-restricted feeding (tRF). Renal histology, fibrosis, and partial epithelial-mesenchymal transition (pEMT) were assessed. RNA sequencing identified pathways, validated in HK-2 cells.

Genetically elevated serum BHB was causally linked to higher renal injury risk. In healthy mice, long-term KD induced renal interstitial fibrosis and maladaptive repair of renal tubular epithelial cells (TECs), characterized by partial EMT, while short-term BHB gavage or tRF reproduced early pro-fibrotic changes (partial EMT and increased fibronectin/collagen I expression) without establishing overt fibrosis. In contrast, in mice with unilateral ischemia-reperfusion injury (UIRI), both BHB and tRF reduced renal damage, renal interstitial collagen deposition and maladaptive repair of TECs. Mechanically, KD upregulated Wnt8b and Junb in healthy kidneys, and BHB treatment promoted β-catenin nuclear translocation in a Wnt8b-dependent manner. Knockdown of Wnt8b or Junb suppressed BHB-induced partial EMT in HK-2 cells. Notably, BHB oppositely regulated Wnt8b in injured kidneys, where it attenuated injury-driven Wnt8b elevation.

Ketosis exhibits a dichotomous renal role: promoting fibrosis through Wnt8b/Junb mediated partial EMT in healthy tissue, while protecting against injury-induced fibrosis. These findings emphasize the context-dependence of KD and caution against its long-term use in healthy individuals.