Kidney Week

Abstract: TH-PO0235

Truncated Form of Angiotensin-Converting Enzyme 2 with Extended Duration of Action Effectively Reduces Kidney Angiotensin II in a Renin-Transgenic Mouse Model of Scleroderma Kidney

Session Information

• CKD: Mechanisms of Injury and Fibrosis - 1
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2203 CKD (Non-Dialysis): Mechanisms

Authors

• Wysocki, Jan, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Jan Wysocki, MD, PhD

• Hassler, Luise, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Luise Hassler, DrMed

• Schulze, Arndt, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Arndt Schulze

• Gulua, Gvantca, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Gvantca Gulua

• Mädge, Laurin Alexander, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Laurin Alexander Mädge

• Sweis, Nabil William, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Nabil William Sweis, MD

• Batlle, Daniel, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Daniel Batlle, MD

Background

Scleroderma kidney (SK) is a rare but devastating complication of scleroderma characterized by accelerated hypertension, proteinuria, and progressive kidney function decline. Renin release from ischemia triggers the SK crisis by the formation of Angiotensin II (Ang II) which causes hypertension and fosters kidney fibrosis. We reasoned that amplification of angiotensin-converting enzyme 2 (ACE2), an enzyme that degrades Ang II, could provide a therapeutic approach by reducing Ang II levels, particularly if achieved within the kidney in addition to the systemic circulation. We bioengineered a shorter form of ACE2 designed to pass the glomerular filtration barrier and tagged with an albumin-binding domain (sACE2-ABD) to extend duration of action. Here, we tested if this form of ACE2 reduces kidney Ang II by amplifying ACE2 within the kidney.

Methods

Research in SK has been limited by the lack of good animal models. We used a renin-transgenic mouse model where human renin reporter gene is introduced in the liver. We found that this mouse model, originally created by Oliver Smithies, recapitulates many of the features of SK, namely severe hypertension, heavy proteinuria, and the classic “onion skinning” of renal arterioles. In this study, 14-week-old male heterozygous RenTg mice were used.

Results

Intraperitoneal (IP) injections of human sACE2-ABD were given every 2-3 days for 4 weeks and resulted in a significant increase in kidney ACE2 activity reflecting kidney uptake after passing the glomerular filtration barrier. This resulted in a significant decrease in kidney Ang II as compared to untreated RenTg controls (Fig 1).

Conclusion

The administration of a novel short form of ACE2 with extended duration of action (sACE2-ABD) that we designed for kidney delivery effectively decreases kidney Ang II in a mouse model of renin-Ang II excess that resembles SK. This suppression of kidney Ang II by ACE2 amplification may be used therapeutically to treat SK.

Funding

• NIDDK Support