Proliferation of renal intercalated cells type A after dietary K restriction involves GDF15 and the stimulation of the H,K‐ATPase type 2

Abstract

Renal adaptation to K+ restriction is a multistep process that involves the inhibition of K+ secretion, the increased expression of the H,K‐ATPase type 2 (HKA2, for review see 1) and the proliferation of type A intercalated cells (A‐IC) in collecting tubules. In other pathophysiological context like in cancer, the HKA2 has been shown to participate in cell proliferation 2,3. Moreover, we have previously identified that the growth factor GDF15 is up‐regulated after K+ restriction in collecting ducts 4. This peptide hormone has already been shown to be of crucial importance in the acidosis‐induced proliferation of the A‐IC 5, but its role during K+ depletion remain to be determined. We aim now at investigating the respective role of both GDF15 and HKA2 in the K+ restriction‐induced proliferation of A‐IC.In contrast to WT mice under a short period (4 days) of low‐K+ diet, GDF15‐null mice exhibit a marked hypokalemia indicating that they do not adapt to this condition. This is related to a lack of proliferation of their A‐IC as shown by PCNA, and Cyclin D1 expression and count of A‐IC number/mm of isolated OMCD. Interestingly, in addition to this lack of K+ restriction induced proliferation, the GDF15‐null mice do not increase the expression of the HKA2 in the OMCD as the WT do. This suggested that he HKA2 expression could be under the control of GDF15 and that this ion pump may participate at the GDF15‐dependent proliferation process. To test this hypothesis, we measured the proliferation rate of A‐IC in HKA2‐null mice (HKA2‐KO) under low‐K+ diet. HKA2‐null mice did not exhibit an increased number of either total or proliferative A‐IC. However, K+ depletion increased the expression of early proliferation markers such as PCNA and cyclin D1 similarly in WT and HKA2‐KO. These results indicate that in the absence of HKA2, the process of A‐IC proliferation is initiated but is promptly aborted. This is confirmed by the fact that the number of apoptotic (TUNEL‐positive) cells in the CD of HKA2‐KO mice is 3 times higher than in that of WT after K+ depletion. According to our recent mathematical model of ion transport in the CD 6, the absence of HKA2 may result in a lower A‐IC cell volume (−20%). Therefore, HKA2 may be relevant during K+ depletion by contributing to the regulation of cell volume during cell division. A dysfunctional increase in cell volume during cell proliferation may result in the activation of ER stress mechanisms and indeed, under a low K+ diet, CHOP expression is almost twice as high in HKA2‐HO mice relative to WT mice.Together, these results revealed a new role for the renal H,K‐ATPase type 2 that may participate in the process of cell proliferation in the context of K+ depletion through a GDF15‐dependent pathway.Support or Funding InformationRecurrent grants from INSERM and from the CNRS.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.