When the researchers added NMN to stimulate SIRT1 activity, they saw decreased HIF-2α levels, suggesting that SIRT1 represses HIF-2α protein activity. To support this, when Huang and colleagues added the SIRT1 suppressor sirtinol, they saw increased HIF-2α protein levels along with increased protein markers of scarring. These findings suggest that the kidney tissue-protective roles of SIRT1 come from HIF-2α protein suppression.
“Together, our data indicate that SIRT1 plays a protective role in renal damage and fibrosis, which is likely due to inhibition of HIF-2α,” said Huang and colleagues. They go on to propose that the SIRT1/HIF-2α axis may provide a new target for the treatment of renal fibrosis and chronic kidney disease.