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: SA-PO423

Renal Tubule-Specific Angiotensinogen Knockout Ameliorates Diabetic Kidney Disease in Type 1 Diabetic Akita Mice

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Yang, Wenxia, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
  • Su, Ke, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
  • Pang, Yuchao, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
  • Liao, Min-Chun, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
  • Peng, Junzheng, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
  • Miyata, Kana N., Saint Louis University, Saint Louis, Missouri, United States
  • Filep, Janos G., Hopital Maisonneuve-Rosemont, Montreal, Quebec, Canada
  • Ingelfinger, Julie R., Massachusetts General Hospital, Boston, Massachusetts, United States
  • Zhang, Shao-Ling, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
  • Chan, John S.D., Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
Background

Angiotensinogen (AGT), the sole precursor of angiotensins in the renin-angiotensin system (RAS), is highly expressed in the renal proximal tubules (RPTs) of mice and patients with diabetic kidney disease (DKD). We reported previously that mice specifically overexpressing Agt in RPTs (Agt-Tg) develop hypertension and kidney injury. However, the pathophysiological roles of the intrarenal RAS in DKD progression is not well-defined. We investigated whether genetic deletion of Agt specifically in renal tubules (RT) could improve kidney injury in type 1 diabetic Akita mice.

Methods

We generated Akita mice with RT-specific Agt knockout (Akita AgtRT KO) by crossbreeding Akita Agtlox/lox mice with AgtRT KO (tubule-specific Pax8-Cre) mice. Male Akita AgtRT KO, Akita Agtlox/lox, non-diabetic Agtlox/lox and AgtRT KO mice were studied at 20 weeks of age. Physiological data, kidney function, and urinary angiotensin II (Ang II) were assessed. Immunostaining on kidney sections, western blotting (WB) and real-time quantitative PCR (RT-qPCR) were performed to assess protein and gene expression in isolated RPTs.

Results

Agt deletion in RT did not significantly affect systolic blood pressure in Akita mice. Fasting blood glucose levels were lower in Akita AgtRT KO vs. Akita mice. Glomerular filtration rate was increased in Akita mice, but was normalized in Akita AgtRT KO mice. The urinary albumin-creatinine ratio (ACR) and Ang II levels were increased in Akita mice, but significantly decreased in Akita AgtRT KO mice. Akita mice exhibited glomerular and tubular hypertrophy, tubular luminal dilation, and necrosis; these abnormalities were markedly attenuated in Akita AgtRT KO mice. Podocyte number (defined by P57 and WT1 staining) was decreased in Akita mice, but was partially restored in Akita AgtRT KO mice. Sodium-glucose cotransporter 2 (SGLT2) expression was lower in Akita AgtRT KO mice than in Akita mice. Urinary glucose excretion was higher in Akita AgtRT KO mice than in Akita mice.

Conclusion

Deletion of Agt in RT decreased hyperglycemia, glomerular hyperfiltration, ACR, kidney injury, and SGLT2 expression in Akita mice, demonstrating that inactivation of the intrarenal RAS attenuates DKD progression, at least in part, via down-regulation of SGLT2 expression.

Funding

  • Government Support – Non-U.S.