Role of transcription factor acetylation in diabetic kidney disease.
Bottom Line: We found that acetylation of p65 and STAT3 was increased in both mouse and human diabetic kidneys.Inhibition of AGE formation in db/db mice by pyridoxamine treatment attenuated proteinuria and podocyte injury, restored SIRT1 expression, and reduced p65 and STAT3 acetylation.Diabetic db/db mice with conditional deletion of SIRT1 in podocytes developed more proteinuria, kidney injury, and acetylation of p65 and STAT3 compared with db/db mice without SIRT1 deletion.
Affiliation: Department of Medicine/Nephrology, Mount Sinai School of Medicine, New York, NY.Show MeSH
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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.