Abstract
The proximal tubule is a particularly important site for ageing-related kidney damage. Sirtuin 1 (SIRT1), an NAD+ (nicotinamide adenine dinucleotide)-dependent deacetylase in the proximal tubule, may be involved in renal injury associated with ageing. However, the mechanisms of SIRT1 regulation remain to be elucidated. We recently reported that angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP)-deficient mice displayed age-associated renal function decline and tubulointerstitial fibrosis. Our data showed that SIRT1 protein expression was reduced in ATRAP-deficient mice, although the relationship between ATRAP deficiency and age-associated renal fibrosis is still not fully understood. It is, therefore, necessary to investigate how ATRAP affects SIRT1 protein expression to resolve ageing-associated kidney dysfunction. Here, since ageing studies are inherently lengthy, we used an ex vivo model of the proximal tubule to determine the role of ATRAP in SIRT1 protein expression. We first generated a clonal immortalised human renal proximal tubule epithelial cell line (ciRPTEC) expressing AT1R and ATRAP. Using this cell line, we demonstrated that ATRAP knockdown reduced SIRT1 protein expression in the ciRPTEC but did not alter SIRT1 mRNA expression. Thus, ATRAP likely mediates SIRT1 protein abundance in ciRPTEC.
Highlights
The proximal tubule is a important site for ageing-related kidney damage
We demonstrated that ATRAP depletion reduced Sirtuin 1 (SIRT1) protein levels only and not SIRT1 mRNA levels in a newly developed ciRPTEC
ATRAP deficiency did not alter SIRT1 mRNA expression either in the presence or absence of serum starvation; even though serum starvation alone induced SIRT1 mRNA accumulation, SIRT1 protein levels were unaltered in the ciRPTEC
Summary
The proximal tubule is a important site for ageing-related kidney damage. Sirtuin 1 (SIRT1), an NAD+ (nicotinamide adenine dinucleotide)-dependent deacetylase in the proximal tubule, may be involved in renal injury associated with ageing. Our data showed that SIRT1 protein expression was reduced in ATRAP-deficient mice, the relationship between ATRAP deficiency and age-associated renal fibrosis is still not fully understood. It is, necessary to investigate how ATRAP affects SIRT1 protein expression to resolve ageingassociated kidney dysfunction. We first generated a clonal immortalised human renal proximal tubule epithelial cell line (ciRPTEC) expressing AT1R and ATRAP Using this cell line, we demonstrated that ATRAP knockdown reduced SIRT1 protein expression in the ciRPTEC but did not alter SIRT1 mRNA expression. Various systemic factors affect SIRT1 expression; for example, serum or nutrient starvation alters the expression level of SIRT1 in cells[18,19,20]
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