Abstract: SA-PO291
Deletion of Angiotensinogen in Renal Tubule Attenuates Diabetic Kidney Disease Progression in Diabetic Mice
Session Information
- Diabetic Kidney Disease: Basic - 2
October 26, 2024 | Location: Exhibit Hall, 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
- Su, Ke, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
- Zhou, Jing, 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
- Leal, Daniel N., Cedars-Sinai Medical Center, Los Angeles, California, United States
- Yamashita, Michifumi, Cedars-Sinai Medical Center, Los Angeles, California, United States
- Miyata, Kana, Saint Louis University, St 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
We previously reported that mice overexpressing angiotensinogen (AGT) in renal proximal tubular cells (RPTCs) developed hypertension and kidney injury Kidney Int. 2006). AGT is highly expressed in renal tubules (RTs) in mice and patients with diabetic kidney disease (DKD). We investigated whether genetic deletion of Agt only in renal tubules (RT) could attenuate DKD progression in type 1 diabetic Akita mice.
Methods
Male Akita mice with RT-specific Agt knockout (Akita RT-Agt KO) at 20 weeks of age were studied +/- selective A1 adenosine receptor inhibitor (A1aRi), which counteracts the effect of RT-Agt KO. Male Akita controls were also studied. We examined immunohistochemistry in kidney sections, electron microscopy to assess glomerulus basement membrane (GBM) thickness and podocyte foot process effacement, intra-vital confocal microscopy to determine the diameter of glomerular afferent and efferent arterioles, and Western blot and real-time qPCR of protein and gene expression in isolated renal proximal tubules (RPTs). HK2 (human immortalized RPTC cell line) cells were also studied.
Results
Akita RT-Agt KO mice had slightly lower systolic blood pressure and fasting blood glucose levels than Akita mice. Akita RT-Agt KO mice displayed significantly attenuated oxidative stress, decreased glomerular hyperfiltration, and decreased glomerulomegaly, tubular injury score, podocyte loss, GBM thickness and podocyte foot process effacement. These findings were associated with decreased urinary albumin/creatinine ratio (UACR), urinary AGT and Ang II levels and SGLT2 expression in RPTs. Intra-vital microscopy revealed decreased afferent arteriole (AA) diameter and increased efferent arteriole (EA) diameter in Akita RT-Agt KO mice cf. Akita mice. Treatment of Akita RT-Agt KO mice with A1aRi increased glomerular filtration rate. In cultured HK2 cells, Ang II stimulated SGLT2 expression, which was attenuated by losartan, NADPH oxidase inhibitors and antioxidants.
Conclusion
RT-specific Agt deletion mitigated DKD progression in Akita mice by reducing glomerular hyperfiltration and UACR, decreasing AA and increasing EA diameter, and decreasing podocyte loss, GBM thickness, podocyte foot process effacement and SGLT2 expression in RTs.
Funding
- Government Support – Non-U.S.