Adipolin protects against renal injury via PPARα-dependent reduction of inflammasome activation

Area of Science:

• Nephrology
• Metabolic research
• Molecular biology

Background:

• Chronic kidney disease (CKD) is a significant global health issue with incompletely understood mechanisms.
• Adipolin, an adipokine, has previously demonstrated benefits in cardiometabolic diseases.
• The specific role of adipolin in the pathogenesis of CKD requires further investigation.

Purpose of the Study:

• To elucidate the role of adipolin in the development and progression of chronic kidney disease.
• To investigate the molecular pathways through which adipolin exerts its effects on renal tissue.
• To determine if adipolin can serve as a therapeutic target for mitigating kidney injury.

Main Methods:

• Utilized a mouse model of subtotal nephrectomy to induce remnant kidney injury.
• Assessed the impact of adipolin deficiency and administration on markers of kidney damage, fibrosis, and oxidative stress.
• Examined the regulation of ketone body production and inflammasome activation in renal tissue.
• Investigated the involvement of the PPARα/HMGCS2 pathway in adipolin's protective effects.

Main Results:

• Adipolin deficiency exacerbated kidney injury, including albuminuria, tubulointerstitial fibrosis, and oxidative stress, via inflammasome activation.
• Adipolin treatment increased ketone body (β-hydroxybutyrate) production and HMGCS2 expression in the remnant kidney.
• Adipolin attenuated inflammasome activation in proximal tubular cells through a PPARα/HMGCS2-dependent mechanism.
• Systemic adipolin administration protected against renal injury in wild-type mice, an effect blunted in PPARα-deficient mice.

Conclusions:

• Adipolin confers protection against renal injury in the context of CKD.
• This protective effect is mediated by the reduction of renal inflammasome activation.
• Adipolin induces HMGCS2-dependent ketone body production via PPARα activation, thereby mitigating kidney damage.