Kidney Week

Abstract: SA-PO0016

Resolution of Diabetic Kidney Disease After Spontaneous Euglycemic Reentry in Diabetic BTBROb/Ob Mice

Session Information

• Development, Stem Cells, and Regenerative Medicine
  October 24, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Development, Stem Cells, and Regenerative Medicine

• 700 Development, Stem Cells, and Regenerative Medicine

Authors

• Qiu, Jiedong, Universitat Heidelberg, Heidelberg, BW, Germany

Jiedong Qiu

• Pastene, Diego O., Universitat Heidelberg, Heidelberg, BW, Germany

Diego O. Pastene, MSc, PhD

• Van Den Born, Jacob, Universitair Medisch Centrum Groningen, Groningen, GR, Netherlands

Jacob Van Den Born, PhD

• van Goor, Harry, Universitair Medisch Centrum Groningen, Groningen, GR, Netherlands

Harry van Goor, PhD

• Krämer, Bernhard K., Universitat Heidelberg, Heidelberg, BW, Germany

Bernhard K. Krämer, DrMed

• Porubsky, Stefan, Universitat Heidelberg, Heidelberg, BW, Germany

Stefan Porubsky, DrMed

• Yard, Benito, Universitat Heidelberg, Heidelberg, BW, Germany

Benito Yard, PhD

Background

Reversal of diabetic kidney disease (DKD) has been reported in patients with type 1 diabetes after pancreatic transplantation, yet its mechanism is largely unknown. This study investigated whether diabetic wild-type and human carnosinase 1–transgenic (hCN1 TG) BTBR^ob/ob mice develop β-cell compensation leading to spontaneous euglycemic re-entry, and whether this process is associated with renal structural and molecular changes, or modified by hCN1 TG.

Methods

Wild-type and hCN1 TG BTBR^ob/ob mice were followed until 48 weeks of age to characterize the development of euglycemic re-entry. Renal outcomes were assessed before and after euglycemic re-entry, including albuminuria and renal histomorphometry. RNA sequencing was performed to identify pathways associated with renal changes during this process. Since hCN1 may increase oxidative burden, we additionally assessed the impact of hCN1 expression on euglycemic re-entry and renal recovery.

Results

Euglycemic re-entry occurred around week 36 and was associated with hyperinsulinemia, increased β-cell mass, and an increased number of Ki67-positive cells within pancreatic islets. Albuminuria gradually declined in both wild-type and hCN1 TG BTBR^ob/ob mice and was accompanied by a significant reduction in mesangial matrix expansion. In contrast, renal corpuscle size, glomerular tuft area, Bowman's space, and glomerular basement membrane thickening did not differ between hyperglycemic mice at week 24 and euglycemic mice at week 48. RNA sequencing revealed significant changes in fibrosis-associated genes, podocyte markers, and markers of tubular injury between hyperglycemic and euglycemic mice. NGAL expression was upregulated in hyperglycemic mice at week 24 and further increased after euglycemic re-entry at week 48, despite the absence of severe histologic tubular damage. This was accompanied by pronounced tubular syndecan-1 expression in 48-week-old BTBR^ob/ob mice.

Conclusion

Spontaneous euglycemic re-entry in BTBR^ob/ob mice is associated with reduced mesangial matrix expansion and declining albuminuria, suggesting partial reversibility of DKD-related glomerular injury. Tubular injury after euglycemic re-entry was not pronounced and may be counterbalanced by a repair response characterized by increased expression of the regenerative protein syndecan-1. hCN1 expression did not alter euglycemic re-entry or the associated renal outcomes.

Acknowledgment

This work was supported by the Research Training Group "DiaMiCom" of the German Research Foundation, the Medical Research Center Groningen, and the Medical Faculty Mannheim at Heidelberg University.

Funding

• Government Support – Non-U.S.