(727.1) Implication of GDF15 in the Context of a Renal Adaptation to a Low Potassium Diet

Poster Board Number: E194

Samia Lasaad (CCentre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Laboratoire de Physiologie Rénale et Tubulopathies, CCentre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Laboratoire de Physiologie Rénale et Tubulopathies), Christine Walter (Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Laboratoire de Physiologie Rénale et Tubulopathies, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Laboratoire de Physiologie Rénale et Tubulopathies), Chloé Rafael (Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Laboratoire de Physiologie Rénale et Tubulopathies, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Laboratoire de Physiologie Rénale et Tubulopathies), Luciana Morla (Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Laboratoire de Physiologie Rénale et Tubulopathies, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Laboratoire de Physiologie Rénale et Tubulopathies), Gilles Crambert (Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Laboratoire de Physiologie Rénale et Tubulopathies, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Laboratoire de Physiologie Rénale et Tubulopathies), Lydie Cheval (Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Laboratoire de Physiologie Rénale et Tubulopathies, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Laboratoire de Physiologie Rénale et Tubulopathies)

Introduction: In the days of hunter-gatherers, the diet was rich in potassium (K+) and low in salt (NaCl) unlike the current modern western diet, in westernized population, which is low in K+ and rich in NaCl. In the long term, a low-K+ diet may contribute to the development of diseases such as hypertension or acidosis. The kidney is the key organ in maintaining the electrolyte balance in our body. Indeed, its role is to adjust by different mechanisms the excretion of electrolytes to our daily intake. These mechanisms involve modifications of ion transporters expression and activity, cellular organization and composition of the renal epithelium (proliferation, trans-differentiation). To face K+ restriction, the kidney adapts its functions to retain K+ by increasing the number of type-A intercalated cells (ICA). Few years ago, a transcriptomic analysis performed by our laboratory revealed that a growth factor, GDF15, was strongly upregulated in renal collecting ducts of K+ depleted animals. Therefore, we hypothesize that GDF15 may be implicated in the renal adaptation to a low-K+ diet, in part by promoting ICA proliferation. 

Material and

Methods: C57BL6J mice wild type or knockout for the Gdf15 gene (GDF15-KO) were used. They were placed under a control or low-K+ diet for 4 days for 1/ GDF15 expression measurement by RT-qPCR in kidney or ELISA in urine and plasma 2/ metabolic analysis (urine excretion, muscle mass and K+content) and 3/ assessment of the number of ICA by immunohistochemistry on microdissected distal tubule.

Results: An increased expression of GDF15 in renal collecting duct, urine and plasma was induced in response to a low-K+ diet.  We showed that under K+ depletion GDF15-KO mice were unable to induce an increase in the number of ICA, showing a role of this growth factor in the cell plasticity of the collecting duct. Compared to WT mice, GDF15-KO mice exhibit a delayed renal adaptation to a K+ restriction reflected by a delayed diminution of urinary K+ excretion. This defect induces hypokalemia in GDF15-KO mice unlike WT mice which remain normokalemic. Interestingly, we have evidence that GDF15 contributes also to the release of intracellular K+ stores in muscles, indicating that this growth factor controls both external and internal K+ balance

Conclusion: Altogether, these results demonstrate that GDF15 is a key factor in the control of the K+ balance.

This study was supported by the Agence Nationale de la Recherche (ANR-21-CE14-0040-01) and by the Fondation pour la Recherche Mamp;eacute;dicale (FRM: DPC20171138949). S.L is a PhD student supported by the Ministamp;egrave;re de lEnseignement Supamp;eacute;rieur, de la Recherche et de lInnovation (MESRI). C.R is supported by grant from the fondation Lefoulon-Delalande.