Kidney Week

Abstract: TH-OR137

Increased Podocyte SIRT1 Function Attenuates Diabetic Kidney Injury

Session Information

• What's New in Diabetic Kidney Disease - I
  November 02, 2017 | Location: Room 273, Morial Convention Center
  Abstract Time: 06:18 PM - 06:30 PM

Category: Diabetes

• 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

• Hong, Quan, Chinese PLA General Hospital , Bei Jing, China

Quan Hong, MD



http://www.301hospital.com.cn/web/showexp/ksdhyjdw/264/1011.html

• Zhang, Lu, Xiamen University Affiliated The First Hospital, Amoy, FuJIan, China

Lu Zhang,

• Das, Bhaskar, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Bhaskar Das,

• Cai, Guangyan, Chinese PLA General Hospital , Bei Jing, China

Guangyan Cai,

• Chen, Xiangmei, Chinese PLA General Hospital , Bei Jing, China

Xiangmei Chen,

• Chuang, Peter Y., Connecticut Kidney Center, LLC, Orange, Connecticut, United States

Peter Y. Chuang,

• He, John C., Icahn School of Medicine at Mount Sinai, New York, New York, United States

John C. He,

• Lee, Kyung, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Kyung Lee,

Background

We previously found that the glomerular expression of Sirtuin-1 (SIRT1) was reduced in human diabetic kidneys and the loss of SIRT1 aggravated albuminuria and worsened kidney disease progression in diabetic mice. SIRT1 encodes an NAD-dependent deacetylase that modifies the activity of key transcriptional regulators affected in diabetic kidneys, including NF-κB and STAT3. Consistent with reduced SIRT1, acetylation of NF-κB and STAT3 was reduced in diabetic kidneys, resulting in their increased activities. In this study we employed genetic and pharmacological means to interrogate whether the increased SIRT1 function is sufficient to attenuate diabetic kidney injury.

Methods

For the genetic approach, we generated doxycline-inducible podocyte-specific overexpression of SIRT1 (Pod-SIRT1^OV) mice, which were further crossed with diabetic OVE26 mice to generate OVE26;Pod-SIRT1^OV. Littermates without SIRT1 transgene (OVE26;WT) and age-matched nondiabetic mice were used as controls. Healthy control, OVE26;WT and OVE26;Pod-SIRT1^OV mice were given dox-supplemented chow starting at 16 weeks of age, at which time the OVE26 mice exhibit pronounced hyperglycemia and proteinuria. For the pharmacological approach, OVE26 mice at 16 weeks of age were treated with either vehicle or novel SIRT1 inhibitor, BF175 (0.4mg/kg daily). All mice were sacrificed at 22 weeks of age for analysis.

Results

6 weeks of Dox administration led to significant reduciton in kidney-to-body weight ratio and urinary albumin excretion in OVE26;Pod-SIRT1^OV in comparison to OVE26;WT mice. Glomerular hypertrophy, mesangial matrix expansion, and podocyte foot process effacement were also markedly reduced in OVE26;Pod-SIRT1^OV mice. Administration of SIRT1 agonist BF175 for 6 weeks similarly led to significant reductions in albuminuria, mesangial matrix expansion, and podocyte foot process effacement in OVE26 mice compared to vehicle treatment. Both OVE26;Pod-SIRT1^OV and OVE26 mice treated with BF175 showed increased podocyte number compared to control OVE26, suggesting that increased SIRT1 function protected against podocyte loss in OVE26 glomeruli.

Conclusion

Our data demonstrates that increased podocyte SIRT1 expression is sufficient to significantly mitigate early diabetic injury and that BF175 is a novel SIRT1 agonist that can be further developed as a potential therapy for early DKD.

Funding

• NIDDK Support