The ketone body β-hydroxybutyrate mitigates the senescence response of glomerular podocytes to diabetic insults

Diabetic kidney disease (DKD) is one of the most common complications of diabetes and is clinically featured by progressive albuminuria, consequent to glomerular destruction that involves podocyte senescence. Burgeoning evidence suggests that ketosis, in particular beta-hydroxybutyrate, exerts a beneficial effect on aging and on myriad metabolic or chronic diseases, including obesity, diabetes and chronic kidney diseases. Its effect on DKD is largely unknown. In vitro in podocytes exposed to a diabetic milieu, beta-hydroxybutyrate treatment substantially mitigated cellular senescence and injury, as evidenced by reduced formation of gamma H2AX foci, reduced staining for senescence-associated-beta-galactosidase activity, diminished expression of key mediators of senescence signaling like p16(INK4A) and p21, and preserved expression of synaptopodin. This beneficial action of beta-hydroxybutyrate coincided with a reinforced transcription factor Nrf2 antioxidant response. Mechanistically, beta-hydroxybutyrate inhibition of glycogen synthase kinase 3fi (GSK3 beta), a convergent point for myriad signaling pathways regulating Nrf2 activity, seems to contribute. Indeed, trigonelline, a selective inhibitor of Nrf2, or ectopic expression of constitutively active mutant GSK3 beta abolished, whereas selective activation of Nrf2 was sufficient for the anti-senescent and podocyte protective effects of beta-hydroxybutyrate. Moreover, molecular modeling and docking analysis revealed that beta-hydroxybutyrate is able to directly target the ATP-binding pocket of GSK3 beta and thereby block its kinase activity. In murine models of streptozotocin-elicited DKD, beta-hydroxybutyrate therapy inhibited GSK3 beta and reinforced Nrf2 activation in glomerular podocytes, resulting in lessened podocyte senescence and injury and improved diabetic glomerulopathy and albuminuria. Thus, our findings may pave the way for developing a fi-hydroxybutyrate-based novel approach of therapeutic ketosis for treating DKD.

Automated summary

The study found that beta-hydroxybutyrate is beneficial for diabetic kidney disease, reducing cellular senescence and injury by inhibiting GSK3 beta and enhancing Nrf2 activity, providing a new approach for treating DKD.