Kidney Week

Abstract: FR-PO0198

Paternal Diabetes Programs Kidney-Driven Hypertension in Offspring via a Sperm miRNA-TET-NGFR Axis

Session Information

• Diabetic Kidney Disease: Metabolic, Mitochondrial, and Inflammatory Mechanisms
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Cardiovascular-Kidney-Metabolic Health

• 601 Cardiovascular-Kidney-Metabolic Health: Basic

Authors

• Wang, Jingyun, Universitat Heidelberg Medizinische Fakultat Mannheim, Mannheim, BW, Germany

Jingyun Wang, MD

• Chen, Xin, Universitat Heidelberg Medizinische Fakultat Mannheim, Mannheim, BW, Germany

Xin Chen, DrMed

• Li, Xitong, Universitat Heidelberg Medizinische Fakultat Mannheim, Mannheim, BW, Germany

Xitong Li, MD, DrMed

• Hocher, Johann-Georg, Universitat Heidelberg Medizinische Fakultat Mannheim, Mannheim, BW, Germany

Johann-Georg Hocher, MD

• Liu, Yvonne Ye, Universitat Heidelberg Medizinische Fakultat Mannheim, Mannheim, BW, Germany

Yvonne Ye Liu

• Krämer, Bernhard K., Universitat Heidelberg Medizinische Fakultat Mannheim, Mannheim, BW, Germany

Bernhard K. Krämer, DrMed

• Wang, Guang, Jinan University Division of Histology and Embryology, Guangzhou, China

Guang Wang, PhD

• Hocher, Berthold, Universitat Heidelberg Medizinische Fakultat Mannheim, Mannheim, BW, Germany

Berthold Hocher, MD, DrMed, PhD

Background

Paternal metabolic disease influences offspring health, but the underlying mechanisms remain incompletely understood. We investigated whether paternal diabetes affects kidney development and blood pressure regulation in offspring through sperm-mediated epigenetic pathways.

Methods

In a mouse model, paternal type 2 diabetes was induced by high-fat/high-sucrose diet plus streptozotocin. Offspring of healthy females were longitudinally assessed for blood pressure, renal histology, and kidney function. Sperm from diabetic fathers underwent small-RNA sequencing. Transcriptomic and methylation profiling were performed in kidneys of male offspring. Functional relevance was tested by kidney-specific NGFR knockdown and embryonic microinjection of a miR-7229-3p agomir. In addition, human datasets on diabetic kidney disease and diabetic sperm were analyzed.

Results

Male, but not female, offspring of diabetic fathers developed progressive arterial hypertension and renal injury despite normal glucose metabolism. This phenotype was characterized by albuminuria, glomerulosclerosis, interstitial fibrosis, and reduced eGFR, and was preceded by impaired embryonic nephrogenesis. Integrative transcriptomic and methylation analyses identified NGFR as a downregulated and hypermethylated candidate gene. Kidney-specific NGFR knockdown reproduced hypertension and renal injury and was associated with suppression of PI3K/AKT/mTOR signaling. Sperm from diabetic fathers showed increased miR-7229-3p, which directly targeted NGFR and the demethylases TET1/2. Embryonic overexpression of miR-7229-3p reproduced the offspring phenotype, including hypertension, renal injury, and promoter hypermethylation of target genes. Human diabetic sperm also displayed altered miRNAs predicted to target this axis, and NGFR expression was reduced in diabetic kidney disease datasets.

Conclusion

Paternal diabetes can program male offspring for impaired kidney development, hypertension, and chronic renal injury through a sperm miRNA–TET–NGFR axis. These findings extend the DOHaD concept to a paternal epigenetic mechanism and identify potential biomarkers and intervention targets for preventing intergenerational renal and hypertensive risk.