Kidney Week

Abstract: PO1715

L-WNK1 Inhibition Protects from Glomerular Injury in Mice

Session Information

• Podocyte Pathobiology: Basic Science Studies and Animal Models
  November 04, 2021 | Location: On-Demand, Virtual Only
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1204 Podocyte Biology

Authors

• Mousseaux, Cyril, CoRaKID - Inserm UMR_S1155, Paris, France

Cyril Mousseaux, MD

• Migeon, Tiffany, CoRaKID - Inserm UMR_S1155, Paris, France

Tiffany Migeon,

• Frère, Perrine, CoRaKID - Inserm UMR_S1155, Paris, France

Perrine Frère,

• Louedec, Liliane, CoRaKID - Inserm UMR_S1155, Paris, France

Liliane Louedec,

• Galichon, Pierre, CoRaKID - Inserm UMR_S1155, Paris, France

Pierre Galichon,

• Hadchouel, Juliette, CoRaKID - Inserm UMR_S1155, Paris, France

Juliette Hadchouel,

Background

The With No lysine (K) kinase L-WNK1 plays a key role in the maintenance of cellular homeostasis in response to variations in osmolarity, intracellular chloride concentration or cell volume. We have shown that L-WNK1 activation in the distal nephron results in hypertension. Other studies showed that the inhibition of L-WNK1 could be beneficial in epileptic diseases and to prevent the metastatic process. However, the preclinical study of a L-WNK1 inhibitor was discontinued due to unacceptable side effects. Therefore, L-WNK1 inhibition can be either beneficial or deleterious depending on the pathology and affected tissue. It is necessary to better define the signalling pathways controlled by L-WNK1 in order to develop targeted therapies with limited secondary effects. In that context, we chose to define the roles played by the kinase in the glomerulus, its predominant site of expression within the kidney.

Methods

We used mice carrying an ubiquitous and heterozygous (L-WNK1^+/-) or podocyte-specific homozygous inactivation of L-WNK1 (NPHS2-Cre;WNK1^lox/lox). We characterised their renal function (plasma urea, creatinine, urine albumin/creatinine) and glomerular structure at baseline and in a model of crescentic glomerulonephritis (CGN) induced by the administration of nephrotoxic serum (NTS-CGN).

Results

L-WNK1 inactivation, either global or podocyte-specific, did not impair glomerular function and structure. After induction of NTS-CGN, the renal function of L-WNK1^+/- mice was improved compared to control ones. We observed a decreased infiltration of macrophages and a lesser stimulation of the expression of fibrotic genes. The same improvement of renal function, associated with a reduced number of glomerular lesions, was observed in NPHS2-Cre;WNK1^lox/lox mice during NTS-CGN. To uncover the underlying mechanisms, we used the immortalised AB8/13 cell line of human podocytes. Our hypotheses were the stimulation of autophagy, a decreased capacity for proliferation and migration and a reduced stimulation of the TRPC6 calcium channel. We have shown that the pharmacological inhibition of L-WNK1 activity by WNK463 resulted in an increased autophagic flux and a decreased migration/proliferation in a wound-healing assay.

Conclusion

In conclusion L-WNK1 inhibition represents a new target for the protection of the podocytes during CGN.

Funding

• Government Support – Non-U.S.