Kidney Week

Abstract: SA-PO423

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

Session Information

• Diabetic Kidney Disease: Basic - II
  November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

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

Wenxia Yang,

• Su, Ke, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada

Ke Su,

• Pang, Yuchao, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada

Yuchao Pang,

• Liao, Min-Chun, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada

Min-Chun Liao,

• Peng, Junzheng, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada

Junzheng Peng,

• Miyata, Kana N., Saint Louis University, Saint Louis, Missouri, United States

Kana N. Miyata,

• Filep, Janos G., Hopital Maisonneuve-Rosemont, Montreal, Quebec, Canada

Janos G. Filep,

• Ingelfinger, Julie R., Massachusetts General Hospital, Boston, Massachusetts, United States

Julie R. Ingelfinger,

• Zhang, Shao-Ling, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada

Shao-Ling Zhang,

• Chan, John S.D., Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada

John S.D. Chan,

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 Agt^RT KO) by crossbreeding Akita Agt^lox/lox mice with Agt^RT KO (tubule-specific Pax8-Cre) mice. Male Akita Agt^RT KO, Akita Agt^lox/lox, non-diabetic Agt^lox/lox and Agt^RT 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 Agt^RT KO vs. Akita mice. Glomerular filtration rate was increased in Akita mice, but was normalized in Akita Agt^RT KO mice. The urinary albumin-creatinine ratio (ACR) and Ang II levels were increased in Akita mice, but significantly decreased in Akita Agt^RT KO mice. Akita mice exhibited glomerular and tubular hypertrophy, tubular luminal dilation, and necrosis; these abnormalities were markedly attenuated in Akita Agt^RT KO mice. Podocyte number (defined by P57 and WT1 staining) was decreased in Akita mice, but was partially restored in Akita Agt^RT KO mice. Sodium-glucose cotransporter 2 (SGLT2) expression was lower in Akita Agt^RT KO mice than in Akita mice. Urinary glucose excretion was higher in Akita Agt^RT 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.