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. 2019 Jan 11;11(1):146.
doi: 10.3390/nu11010146.

SIRT1 Attenuates Kidney Disorders in Male Offspring Due to Maternal High-Fat Diet

Long T Nguyen  1 , Crystal H Mak  2 , Hui Chen  3   4 , Amgad A Zaky  5 , Muh G Wong  6 , Carol A Pollock  7 , Sonia Saad  8   9
Affiliations

SIRT1 Attenuates Kidney Disorders in Male Offspring Due to Maternal High-Fat Diet

Long T Nguyen et al. Nutrients. .

Abstract

Maternal obesity has been associated with kidney disorders in male offspring. Our previous studies have demonstrated that Sirtuin (SIRT)1, an essential regulator of metabolic stress responses, is suppressed in the offspring as the result of maternal high-fat diet (HFD) consumption, which is likely to underpin the adverse metabolic and renal outcomes. To examine if SIRT1 overexpression or activation early in life can protect the offspring kidney, wild-type (WT) and transgenic (Tg) offspring were born to the same diet-induced obese female C57BL/6 mice through breeding with hemizygous SIRT1-transgenic (Tg) male mice and examined for renal pathological changes. In separate experiments, SIRT1 activator SRT1720 (25 mg/kg/2 days i.p) was administrated in WT offspring over 6 weeks of postnatal high-fat diet exposure. The results show that offspring born to obese dams have increased kidney weight, higher levels of renal triglycerides, and increased expression of oxidative stress, inflammatory, and fibrotic markers, as well as increased albuminuria compared to offspring of control dams. Both SIRT1 overexpression and SRT1720 treatment attenuated renal lipid contents and expression of lipogenesis, oxidative stress, and inflammatory markers; however, fibrosis was modestly reduced and albuminuria was not affected. The findings suggest that SIRT1 therapy can ameliorate some pathological mechanisms of kidney programming due to maternal obesity but may not be sufficient to prevent the resulting chronic kidney injury.

Keywords: Obesity; chronic kidney disease; foetal programming; sirtuin.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Animal models of SIRT1 overexpression (A) and activation (B) in offspring. SIRT: sirtuin; MC: offspring of chow-fed dams; MHF: offspring of HFD-fed dams; MHFS: MHF offspring with SIRT1 overexpression. OC: chow-fed offspring; OHF: HFD-fed offspring; WT: wild-type; Tg: transgenic, HFD: high-fat diet.
Figure 2
Figure 2
SIRT1 overexpression reduces kidney weight and lipid accumulation in offspring born to obese dams. (A) Kidney weight (n = 11–26). (B) Kidney triglyceride level (n = 6). (C) SIRT1 expression and activity (n = 6). (D) The expression of downstream markers of SIRT1 (n = 6). Data are expressed by mean ± SEM or box plot (min to max, the central lines indicate the median). SIRT: sirtuin; PGC-1α: peroxisome proliferator-activated receptor gamma coactivator 1 alpha; SREBP-1c: sterol regulatory element-binding protein, ChREBP: carbohydrate-responsive element-binding protein; MC: offspring of chow-fed dams; MHF: offspring of HFD-fed dams; MHFS: MHF offspring with SIRT1 overexpression. * p < 0.05, *** p < 0.001.
Figure 3
Figure 3
SIRT1 overexpression attenuates renal oxidative stress in offspring born to obese dams. (A) mRNA expression of oxidative stress markers (n = 6). (B) Protein expression of antioxidant enzymes. (C) Immunohistochemistry (IHC) staining and quantification of 8-hydroxy-2′-deoxyguanosine (8-OHdG) (n = 6). Data are presented as mean ± SEM or box plot (min to max, the central lines indicate the median). SIRT: sirtuin; iNOS inducible nitric oxide synthase; COX2: prostaglandin-endoperoxide synthase; NOX: NADPH oxidase; MnSOD: manganese superoxide dismutase; GPx: Glutathione peroxidase; MC: Offspring of chow-fed dams; MHF: offspring of HFD-fed dams; MHFS: MHF offspring with SIRT1 overexpression. * p < 0.05, ** p < 0.01.
Figure 4
Figure 4
SIRT1 overexpression reduces markers of macrophage but not fibrosis and albuminuria in offspring born to obese dams. (A) mRNA expression of inflammation. (B) IHC staining quantification of fibrotic markers (n = 6). (C) Urinary albumin creatinine ratio UACR (n = 6). Data are presented as mean ± SEM or box plot (min to max, the central lines indicate the median). MCP: Macrophage chemotactic protein; TNFα: Tumour necrosis factor alpha; COL: collagen; FN: fibronectin. MC: offspring of chow-fed dams; MHF: offspring of HFD-fed dams; MHFS: MHF offspring with SIRT1 overexpression. * p < 0.05, ** p < 0.01.
Figure 5
Figure 5
SRT1720 suppresses renal lipid accumulation in offspring due to maternal and postnatal HFD consumption. (A). Kidney weight (n = 9–17). (B) Kidney triglyceride level (n = 8). (C) SIRT1 expression and activity. (D) mRNA expression of SIRT1 downstream markers (n = 8). Data are expressed by mean ± SEM or box plot (min to max, the central lines indicate the median). SIRT: sirtuin; PGC-1α: peroxisome proliferator-activated receptor gamma coactivator 1 alpha; SREBP-1c: sterol regulatory element-binding protein, ChREBP: carbohydrate-responsive element-binding protein; MC: offspring of chow-fed dams; OC: chow-fed offspring; MHF: offspring of HFD-fed dams; OHF: HFD-fed offspring; S: SRT1720. * p < 0.05, ** p < 0.01.
Figure 6
Figure 6
SRT1720 attenuates renal oxidative stress in offspring due to maternal and postnatal HFD consumption. (A) mRNA expression of oxidative stress markers (n = 8). (B) Protein expression of antioxidant enzymes (n = 8). (C) IHC staining and quantification of 8-hydroxy-2′-deoxyguanosine (8-OHdG) (n = 8). Data are presented as mean ± SEM or box plot (min to max, the central lines indicate the median). iNOS inducible nitric oxide synthase; COX2: prostaglandin-endoperoxide synthase; NOX: NADPH oxidase; MnSOD: manganese superoxide dismutase; GPx: Glutathione peroxidase; MC: offspring of chow-fed dams; OC: chow-fed offspring; MHF: offspring of HFD-fed dams; OHF: HFD-fed offspring; V or VEH: vehicle control, S or SRT: SRT1720. * p < 0.05.
Figure 7
Figure 7
SRT1720 attenuates renal inflammation and fibrosis but not the urinary albumin creatinine ratio in offspring due to maternal and postnatal HFD consumption. (A) mRNA expression of inflammatory markers. (B) Immunohistochemistry quantification of fibrotic markers (n = 8). (C) Urinary albumin creatinine ratio UACR (n = 8). Data are presented as mean ± SEM. MCP: Macrophage chemotactic protein; TNFα: Tumour necrosis factor alpha; COL: collagen; FN: fibronectin. MC: offspring of chow-fed dams; OC: chow-fed offspring; MHF: offspring of HFD-fed dams; OHF: HFD-fed offspring; S: SRT1720. * p < 0.05, ** p < 0.01.
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