Kidney-specific Overexpression of Sirt1 Protects against Acute Kidney Injury by Retaining Peroxisome Function

Abstract

Sirt1, a NAD-dependent protein deacetylase, is reported to regulate intracellular metabolism and attenuate reactive oxidative species (ROS)-induced apoptosis leading to longevity and acute stress resistance. We created transgenic (TG) mice with kidney-specific overexpression of Sirt1 using the promoter sodium-phosphate cotransporter IIa (Npt2) driven specifically in proximal tubules and investigated the kidney-specific role of Sirt1 in the protection against acute kidney injury (AKI). We also elucidated the role of number or function of peroxisome and mitochondria in mediating the mechanisms for renal protective effects of Sirt1 in AKI. Cisplatin-induced AKI decreased the number and function of peroxisomes as well as mitochondria and led to increased local levels of ROS production and renal tubular apoptotic cells. TG mice treated with cisplatin mitigated AKI, local ROS, and renal tubular apoptotic tubular cells. Consistent with these results, TG mice treated with cisplatin also exhibited recovery of peroxisome number and function, as well as rescued mitochondrial function; however, mitochondrial number was not recovered. Immunoelectron microscopic findings consistently demonstrated that the decrease in peroxisome number by cisplatin in wild type mice was restored in transgenic mice. In HK-2 cells, a cultured proximal tubule cell line, overexpression of Sirt1 rescued the cisplatin-induced cell apoptosis through the restoration of peroxisome number, although the mitochondria number was not restored. These results indicate that Sirt1 overexpression in proximal tubules rescues cisplatin-induced AKI by maintaining peroxisomes number and function, concomitant up-regulation of catalase, and elimination of renal ROS levels. Renal Sirt1 can be a potential therapeutic target for the treatment of AKI.

Sirtuin 1 inhibition delays cyst formation in autosomal-dominant polycystic kidney disease

“…A recent study reports that kidney-specific SIRT1 overexpression in proximal tubules does not appear to make mice susceptible to kidney cysts, but instead is protective against the consequence of ischemic and obstructive injury. These data suggest that overexpression of SIRT1 in proximal tubules, in the presence of WT PC1, may not result in renal cyst formation (32). Thus, the most plausible explanation for a pathological role of SIRT1 in renal cystogenesis is that PC1 mutations fundamentally change renal epithelial cells essential for cyst formation, and this process is modulated by SIRT1 activity.…”

Endotoxin Uptake by S1 Proximal Tubular Segment Causes Oxidative Stress in the Downstream S2 Segment

“…Using immunofluorescence microscopy, we show, in Figure 9, that endotoxin uptake in S1 is accompanied by a robust expression of HO-1 and SIRT1, two cytoprotective molecules known to oppose oxidative stress. 23,24 In contrast, S2 tubules, while also up regulating HO-1 expression, failed to show any significant SIRT1 expression. We also examined peroxisomal integrity after endotoxin administration.…”

“…Indeed, HO-1 and the histone deacetylase SIRT1 have been reported to convey protection in various models of AKI. 23,24,34,35 In our model of endotoxemia, the S1 segment acts as the "sensor" of endotoxin in the filtrate and, as such, autoprotects itself while simultaneously signaling to neighboring segments. This function of S1 segments is remarkably similar to that of Kupffer cells in the liver, which also signal the presence of endotoxin to neighboring hepatocytes.…”

Cellular and Molecular Mechanisms of AKI

“…The role of peroxisomes in AKI is further substantiated by findings that overexpression of Sirt1, an NADdependent protein deacetylase that regulates intracellular metabolism and attenuates ROS-induced cell death, mediates these protective effects through maintaining peroxisomal number and function. 72 …”