Kidney Week

Abstract: TH-PO423

Progressive Tubulointerstitial Damage through Constitutive Activation of the NF-kB Pathway in Renin Lineage Cells

Session Information

• Development, Organoids, Injury, and Regeneration
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Development, Stem Cells, and Regenerative Medicine

• 600 Development, Stem Cells, and Regenerative Medicine

Authors

• Simonova, Irina, Universitatsklinikum Carl Gustav Carus, Dresden, Sachsen, Germany

Irina Simonova, MSc

• Gembardt, Florian, Universitatsklinikum Carl Gustav Carus, Dresden, Sachsen, Germany

Florian Gembardt, PhD

• Steglich, Anne, Universitatsklinikum Carl Gustav Carus, Dresden, Sachsen, Germany

Anne Steglich

• Sradnick, Jan, Universitatsklinikum Carl Gustav Carus, Dresden, Sachsen, Germany

Jan Sradnick, PhD

• Todorov, Vladimir T., Universitatsklinikum Carl Gustav Carus, Dresden, Sachsen, Germany

Vladimir T. Todorov, MD, PhD

• Hugo, Christian, Universitatsklinikum Carl Gustav Carus, Dresden, Sachsen, Germany

Christian Hugo, MD, PhD

Group or Team Name

• Working Group Hugo, University Clinic Carl Gustav Carus, Dresden.

Background

NF-κB (Nuclear factor κB) is a family of related transcription factors that play a pivotal role in many inflammatory processes including immune mediated kidney disease potentially linking inflammation,injury or regeneration. Various inflammatory signals activate NF-κB through TNF (tumor necrosis factor) and other cyto- and chemokine,B or T cell receptors.Activated IKK (inhibitor of NF-kB kinase) complex plays a major role in degradation of IκBα(NF-kB inhibitor α)after which the NF κB dimer p65/ RelA translocates to the nucleus and activates inflammatory genes.We investigated the impact of NF-κB(IKK) activation specifically in RLC (renin-lineage cells) well known as an important niche involved in regeneration and replacement of damaged mesangial and epithelial cells of the murine kidney. RLC of adult mice make up about 10% of all kidney cells including JGA,mesangial,epithelial and smooth-muscle cells

Methods

We created transgenic mouse line mRen-Cre-IKKca with targeted overexpression of IKK2 in RLCs leading to constitutive activation of the NF-kB pathway. The data were collected at 1, 3 and 6 months of age for IKK2 and WT male and female animals. We analyzed functional parameters, morphological changes (PAS) and the expression of Renin,aSMA,Na+/K+ ATPase,SLC4A4,AQP1,AQP2, AE1,Calb1, serum and 24h urine samples

Results

Data showed in IKK2 mice significant increase of urine volumes (in WT µ=1850ml,in IKK2 µ=5186ml) as well as α1-Microglobulin amounts in 24h urine(in WT µ=1.12µg,in IKK2 µ=14.24µg) already at the age of 3M compared to WT but slight rise of urine albumin amounts only at 6M.PAS stainings demonstrated progressive tubulo-interstitial damage solely in mRen-Cre-IKKca mice starting at 3M of age.IHC staining of AQP2 (principal cells in collecting duct) was significantly reduced at 3M and 6M compared to WT.Other markers will clarify these changes

Conclusion

Our study reveals a profound renal phenotype of mice with NF-kB pathway activation specifically in RLCs linking this inflammation signaling with progressive injury and insufficient regeneration.The transgenic mice developed tubulo-interstitial damage starting at 3M of age(increased α1-Microglobulin,PAS,concomitant reduction of AQP-2) while only slight albumin rise at 6M indicates that glomerular changes appear later and less severe

Funding

• Government Support – Non-U.S.