Role of transcription factor acetylation in diabetic kidney disease.
Bottom Line: Here, we determined the roles of Sirt1 and the effect of NF-κB (p65) and STAT3 acetylation in DN.Our findings strongly support a critical role for p65 and STAT3 acetylation in DN.Targeting protein acetylation could be a potential new therapy for DN.
Affiliation: Department of Medicine/Nephrology, Mount Sinai School of Medicine, New York, NY.Show MeSH
Related in: MedlinePlus
Mentions: Next we determined whether the inhibition of AGE formation in db/db diabetic mice using a specific AGE inhibitor, PYR, restores Sirt1 expression, reduces TF acetylation, and attenuates podocyte apoptosis and proteinuria in diabetic db/db mice. In Supplementary Table 3, we summarize the body weight, kidney weight, and blood glucose concentrations of db/m and db/db mice treated with either vehicle or PYR. We found that the kidney weights of db/db mice treated with vehicle were higher than db/m mice treated with vehicle, but kidney hypertrophy was prevented in db/db mice treated with PYR. Diabetic db/db mice treated with vehicle developed significant proteinuria, glomerular hypertrophy, mesangial expansion, and podocyte loss compared with nondiabetic db/m mice (Fig. 4A–G). However, db/db mice treated with PYR developed less proteinuria, glomerular hypertrophy, mesangial expansion, and podocyte loss than db/db mice treated with vehicle (Fig. 4A–G). SIRT1 expression was partially restored in the glomeruli of db/db mice treated with PYR but not in db/db mice treated with vehicle (Fig. 5A–D). Consistent with previously findings, synaptopodin expression also was reduced in diabetic kidneys but was restored by PYR treatment (Fig. 5A–D). By immunostaining, we found that the acetylation status of both p65 and STAT3 in the glomeruli of db/db mice treated with PYR was lower than that in db/db mice treated with vehicle (Fig. 5E–H). Taken together, these data suggest that renal protection afforded by PYR is associated with the restoration of SIRT1 expression and inhibition of TF acetylation. However, whether suppression of SIRT1 and increased TF acetylation contribute to DN remains to be determined.
Affiliation: Department of Medicine/Nephrology, Mount Sinai School of Medicine, New York, NY.