Abstract
Aging is associated with an increased incidence and prevalence of renal glomerular diseases. Sirtuin (Sirt) 6, a nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase, has been shown to protect against multiple age-associated phenotypes; however it is unknown whether Sirt6 has a direct pathophysiologic role in the kidney. In the present study, we demonstrate that Sirt6 is expressed in the kidney and aging Sirt6-deficient mice exhibit renal hypertrophy with glomerular enlargement. Sirt6 deletion induces podocyte injury, including decreases in slit diaphragm proteins, foot process effacement, and cellular loss, resulting in proteinuria. Knockdown of Sirt6 in cultured primary murine podocytes induces shape changes with loss of process formation and cell apoptosis. Moreover, Sirt6 deficiency results in progressive renal inflammation and fibrosis. Collectively, these data provide compelling evidence that Sirt6 is important for podocyte homeostasis and maintenance of glomerular function, and warrant further investigation into the role of Sirt6 in age-associated kidney dysfunction.
Highlights
Renal glomerular diseases, including glomerular hypertension, diabetic nephropathy, and focal segmental glomerulosclerosis (FSGS), affect public health [1]
The level of acetylation of H3K56, which is a substrate of Sirt6 [18], was significantly increased in Sirt6 deficient kidney compared to Wilms’ tumor (WT) kidney (Fig. 1C, lower panel)
We have demonstrated that Sirt6 is expressed in the mouse kidney and its deletion causes progressive renal inflammation, glomerular hypertrophy, loss of podocyte structure and function, and fibrosis
Summary
Renal glomerular diseases, including glomerular hypertension, diabetic nephropathy, and focal segmental glomerulosclerosis (FSGS), affect public health [1]. Investigators have explored aging-related pathways in the development of glomerular diseases, and results of these studies have led to the identification of a critical role for Klotho, a well-known anti-aging molecule, in sup-pressing renal NF-κB activation and inflammation [3], inhibiting proteinuria and decreasing renal fibrosis [4], and attenuating renal hypertrophy and glomerular injury [5]. These results suggest that reduction of Klotho level during aging may contribute to renal diseases such as diabetic nephropathy. Progress in the field of molecular mechanisms contributing to aging has increased exponentially in recent years, with the impact of many of these signaling pathways on renal function remaining poorly understood
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