GDF15 mediates renal cell plasticity in response to potassium depletion

Abstract

A low potassium (K⁺) intake is a common situation in the population of the Westernized countries where processed food is prevalent in the diet. Here, we show that expression of GDF15, a TGFβ-related growth factor, is increased in renal tubular segments and gut parts of mice in response to low-K⁺ diet leading to a systemic elevation of its plasma and urine concentration. In human, under mild dietary K⁺ restriction, we observed that urine GDF15 excretion is correlated with plasma K⁺ level. Conversely to WT mice, adaptation to K⁺ restriction of GDF15-KO mice is not optimal, they do not increase their number of type A intercalated cell, responsible for K⁺ retention, and have a delayed renal K⁺ retention, leading to early development of hypokalemia. This renal effect of GDF15 depends on ErBb2 receptor, whose expression is increased in the kidney collecting ducts. We also observe that, in the absence of GDF15, the release of K⁺ by the muscles is blunted which is compensated by a loss of muscle mass. Thus, in this study, we showed that GDF15 plays a central role in the response to K⁺ restriction by orchestrating the modification of the cell composition of the collecting duct.