ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on X

Kidney Week

Abstract: FR-PO373

Overexpression of Adiponectin, via an Adipocyte Specific Promoter, Confers Metabolic Benefits and Transient Improvements in Urine Albumin-Creatinine Ratio (UACR)

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Seth, Asha, AstraZeneca PLC, Cambridge, United Kingdom
  • Liljeblad, Mathias, AstraZeneca, Gothenburg, Sweden
  • Haschler, Timo Nicolas, AstraZeneca PLC, Cambridge, United Kingdom
  • Tonelius, Pernilla, AstraZeneca, Gothenburg, Sweden
  • Choi, Su Mi, AstraZeneca, Gaithersburg, Maryland, United States
  • Liarte Marin, Elena, AstraZeneca, Gaithersburg, Maryland, United States
  • Bousfield, Philip Marcus, AstraZeneca, Gaithersburg, Maryland, United States
  • Kurasawa, James H., AstraZeneca, Gaithersburg, Maryland, United States
  • Nuñez Duran, Esther, AstraZeneca, Gothenburg, Sweden
  • Basak, Jayati, AstraZeneca PLC, Cambridge, United Kingdom
  • Boianelli, Alessandro, AstraZeneca, Gothenburg, Sweden
  • Svenningsen, Per, Syddansk Universitet Det Sundhedsvidenskabelige Fakultet, Odense, Syddanmark, Denmark
  • Laerkegaard Hansen, Pernille B., AstraZeneca, Gothenburg, Sweden
  • Williams, Julie, AstraZeneca, Gothenburg, Sweden
  • Ikeda, Yasuhiro, AstraZeneca, Gothenburg, Sweden
Background

Adiponectin is an endocrine factor synthesized and released from adipose tissue. Clinical and pre-clinical data have linked low adiponectin levels with the acceleration of kidney disease. However, adiponectin’s complex structure and multiple molecular forms have stunted therapeutic approaches to augment adiponectin signalling. We hypothesized that in-vivo overexpression of adiponectin using adipocyte specific AAV vectors would lead to extended increased systemic exposure of functional adiponectin forms.

Methods

We engineered an adipocyte-specific promoter and achieved AAV8 uptake and overexpression of adiponectin in vivo with exposure for up to 12 weeks in plasma. We evaluated the effects of adiponectin overexpression on metabolism and kidney function in the BTBR ob/ob mouse model of dyslipidaemia and diabetic kidney disease.

Results

In human glomerular endothelial cells and iPS differentiated podocytes, protective effects of adiponectin signalling were observed in in vitro disease models. Mice treated with AAV-adiponectin displayed a decrease in body weight change from the first week after treatment up to 9 weeks in BTBR ob/ob mice. In addition, adiponectin overexpression also decreased the urinary albumin to creatinine ratio 3 weeks after treatment; however, this effect was lost at later time points. At termination, AAV-adiponectin-treated obese animals had significantly decreased plasma cholesterol, liver triglyceride levels, and a decreased liver weight as a proportion of body weight. The effect of AAV-adiponectin overexpression on body weight gain was reproduced in a second study in which WT mice were treated with HFD for 10 weeks.

Conclusion

Adiponectin overexpression can reduce body weight gain and improve metabolic parameters in the liver. Overexpression of adiponectin can transiently decrease kidney damage, as assessed by UACR, but further work is required to determine how to maintain the kidney protective effects of adiponectin.

Funding

  • Commercial Support – AstraZeneca