GDF15 triggers homeostatic proliferation of acid-secreting collecting duct cells.

Although adult kidney cells are quiescent, enlargement of specific populations of epithelial cells occurs during repair and adaptive processes. A prerequisite to the development of regenerative therapeutics is to identify the mechanisms and factors that control the size of specific populations of renal cells. Unfortunately, in most cases, it is unknown whether the growth of cell populations results from transdifferentiation or proliferation and whether proliferating cells derive from epithelial cells or from circulating or resident progenitors. In this study, the mechanisms underlying the enlargement of the acid-secreting cell population in the mouse kidney collecting duct in response to metabolic acidosis was investigated. Acidosis led to two phases of proliferation that preferentially affected the acid-secreting cells of the outer medullary collecting duct. All proliferating cells displayed polarized expression of functional markers. The first phase of proliferation, which started within 24 h and peaked at day 3, was dependent on the overexpression of growth differentiation factor 15 (GDF15) and cyclin D1 and was abolished when phosphatidylinositol-3 kinase and mammalian target of rapamycin were inhibited. During this phase, cells mostly divided along the tubular axis, contributing to tubule lengthening. The second phase of proliferation was independent of GDF15 but was associated with induction of cyclin D3. During this phase, cells divided transversely. In summary, acid-secreting cells proliferate as the collecting duct adapts to metabolic acidosis, and GDF15 seems to be an important determinant of collecting duct lengthening.