AMPK-dependent autophagy mediates the renoprotective effects of phenolic-rich grape pomace extract in obesity-induced nephropathy

Abstract

Background

Obesity is a major risk factor for chronic kidney disease. High-fat diet (HFD) consumption promotes renal lipotoxicity, inflammation, oxidative stress, fibrosis, and impaired adenosine monophosphate-activated protein kinase (AMPK) signaling. We previously demonstrated that grape pomace extract (GPE), rich in phenolic compounds, ameliorates obesity-associated metabolic alterations and protects against renal injury in HFD-fed mice.

Obesity is a major risk factor for chronic kidney disease. High-fat diet (HFD) consumption promotes renal lipotoxicity, inflammation, oxidative stress, fibrosis, and impaired adenosine monophosphate-activated protein kinase (AMPK) signaling. We previously demonstrated that grape pomace extract (GPE), rich in phenolic compounds, ameliorates obesity-associated metabolic alterations and protects against renal injury in HFD-fed mice.

Objective

This study investigated whether the renoprotective effects of GPE are mediated through AMPK activation and autophagy modulation.

This study investigated whether the renoprotective effects of GPE are mediated through AMPK activation and autophagy modulation.

Methods

Male C57BL/6 mice were fed either a standard diet (16% kcal from fat) or an HFD (60% kcal from fat), with or without GPE (300 mg/kg/day), for 16 weeks. To determine the role of AMPK signaling, a subset of animals received Compound C, a selective AMPK inhibitor (20 mg/kg/day), during the last 4 weeks of treatment (Protocol approval No 286/2026, Institutional Animal Care and Use Committee of the School of Medical Science, Universidad Nacional de Cuyo). Renal function, histopathological alterations, lipid accumulation, inflammatory responses, and autophagy-related markers were evaluated.

Male C57BL/6 mice were fed either a standard diet (16% kcal from fat) or an HFD (60% kcal from fat), with or without GPE (300 mg/kg/day), for 16 weeks. To determine the role of AMPK signaling, a subset of animals received Compound C, a selective AMPK inhibitor (20 mg/kg/day), during the last 4 weeks of treatment (Protocol approval No 286/2026, Institutional Animal Care and Use Committee of the School of Medical Science, Universidad Nacional de Cuyo). Renal function, histopathological alterations, lipid accumulation, inflammatory responses, and autophagy-related markers were evaluated.

Results

HFD feeding induced visceral adiposity, hyperglycemia, dyslipidemia, renal lipid accumulation, impaired kidney function, tubular and glomerular injury, and fibrosis. GPE supplementation attenuated obesity and markedly reduced renal damage which was associated with enhanced AMPK activation and autophagic flux. In contrast, pharmacological inhibition of AMPK abolished the protective effects of GPE, resulting in aggravated renal damage, reduced autophagy, increased lipid deposition, and enhanced expression of inflammatory and fibrotic markers.

HFD feeding induced visceral adiposity, hyperglycemia, dyslipidemia, renal lipid accumulation, impaired kidney function, tubular and glomerular injury, and fibrosis. GPE supplementation attenuated obesity and markedly reduced renal damage which was associated with enhanced AMPK activation and autophagic flux. In contrast, pharmacological inhibition of AMPK abolished the protective effects of GPE, resulting in aggravated renal damage, reduced autophagy, increased lipid deposition, and enhanced expression of inflammatory and fibrotic markers.

Conclusion

These findings demonstrate that AMPK activation is required for the renoprotective effects of GPE in obesity-induced nephropathy and identify AMPK-dependent autophagy as a key mechanism underlying the beneficial impact of grape-derived phenolic compounds. Our results support the potential of grape pomace bioactives as nutritional strategies to mitigate obesity-associated renal dysfunction.

These findings demonstrate that AMPK activation is required for the renoprotective effects of GPE in obesity-induced nephropathy and identify AMPK-dependent autophagy as a key mechanism underlying the beneficial impact of grape-derived phenolic compounds. Our results support the potential of grape pomace bioactives as nutritional strategies to mitigate obesity-associated renal dysfunction.