GDF15 mediates renal cell plasticity in response to potassium depletion in mice

To understand the mechanisms involved in the response to a low-K⁺ diet (LK), we investigated the role of the growth factor GDF15 and the ion pump H,K-ATPase type 2 (HKA2) in this process.

Male mice of different genotypes (WT, GDF15-KO, and HKA2-KO) were fed an LK diet for different periods of time. We analyzed GDF15 levels, metabolic and physiological parameters, and the cellular composition of collecting ducts.

Mice fed an LK diet showed a 2-4-fold increase in plasma and urine GDF15 levels. Compared to WT mice, GDF15-KO mice rapidly developed hypokalemia due to impaired renal adaptation. This is related to their 1/ inability to increase the number of type A intercalated cells (AIC) and 2/ absence of upregulation of H,K-ATPase type 2 (HKA2), the two processes responsible for K⁺ retention. Interestingly, we showed that the GDF15-mediated proliferative effect on AIC was dependent on the ErbB2 receptor and required the presence of HKA2. Finally, renal leakage of K⁺ induced a reduction in muscle mass in GDF15-KO mice fed LK diet.

In this study, we showed that GDF15 and HKA2 are linked and play a central role in the response to K⁺ restriction by orchestrating the modification of the cellular composition of the collecting duct.