ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on X

Kidney Week

Abstract: FR-PO757

Deciphering the Role of Slit-Diaphragm Interactors in Podocyte Integrity and Glomerular Diseases

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

  • Khbouz, Badr, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Dumoulin, Bernhard, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Wu, Hui, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Huber, Tobias B., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Grahammer, Florian, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
Background

Renal filtration is determined by the slit-diaphragm (SD), a cell-cell junction between the foot processes of renal podocytes. Through an unbiased screening approach, we have identified several interaction partners of the SD core proteins Nephrin, Neph1 and Podocin. Here, we investigate the role of two of them: the natriuretic peptide receptor 3 (NPR3), a member of the ANP Receptors, and MER Proto-Oncogene, Tyrosine Kinase (MERTK), a member of the TAM receptor tyrosine kinases.

Methods

Podocyte specific knockout C57BL/6 mice (NPR3-/-) and (MERTK -/-) were used. NPR3-/- and WT mice (n=54) were exposed (or not) to unilateral nephrectomy followed by Deoxycorticosterone acetate (DOCA) high salt hypertension model. After weekly measurements of blood pressure (BP) and albuminuria (6 weeks), the kidneys and blood were harvested for functional and tissue assessment. Next NPR3-/- and WT mice (n=20) were subjected to the Adriamycin nephropathy model, 10 days’ post treatment, urine, blood and kidney were collected for analysis. Lastly, MERTK-/- and WT mice (n=26) were exposed to nephrotoxic serum induced nephritis (NTN) model, with the assessment of albuminuria and glomerular damage 4 and 8 days’ post-treatment.

Results

Following DOCA administration, the systolic BP, kidney weight, glomerular tuft volume, and albuminuria were increased in treated animals compared to controls (p<0,01), NPR3-/- mice showed intermedium profile between WT and controls. Adriamycin treatment induced a mild albuminuria in WT, unlike NPR3-/- mice (p<0,05). Blood Urea Nitrogen (BUN) was not different. Following NTN treatment, albuminuria levels and glomerular damage were increased in both genotypes, yet this phenotype was significantly more severe in MERTK -/- mice compared to WT animals.

Conclusion

Given that both NPR3 and MERTK are involved in cellular signaling, these results suggest a potential role of these interactors in the dynamic adaptation of podocyte and/or SD function. The molecular mechanisms behind these dynamic changes are currently being deciphered.

Funding

  • Government Support – Non-U.S.