Abstract
Mitogen-activated protein kinases (MAPKs) are intracellular molecules regulating a wide range of cellular functions, including proliferation, differentiation, apoptosis, cytoskeleton remodeling and cytokine production. MAPK activity has been shown in normal kidney, and its over-activation has been demonstrated in several renal diseases. The extracellular signal-regulated protein kinases (ERK 1,2) signalling pathway is the first described MAPK signaling. Intensive investigations have demonstrated that it participates in the regulation of ureteric bud branching, a fundamental process in establishing final nephron number; in addition, it is also involved in the differentiation of the nephrogenic mesenchyme, indicating a key role in mammalian kidney embryonic development. In the present manuscript, we show that ERK1,2 signalling mediates several cellular functions also in mature kidney, describing its role along the nephron and demonstrating whether it contributes to the regulation of ion channels and transporters implicated in acid-base and electrolytes homeostasis.
Highlights
The Mitogen-activated protein kinases (MAPKs) cascade is a signal transduction common to several cell types, and it is involved in many biological processes, including cell proliferation, differentiation, development, and apoptosis [1].The ERK1,2 signalling is the first identified MAPK signalling [2]
MAPK signalling is activated by a wide range of stimuli in mature kidney; these pathways have been shown to be critical in mediating cell response to different types of stress and injuries and to play a role in the pathophysiology of several diseases
We propose that in patients treated with calcineurin inhibitors and with drugs interfering with ERK1,2 signalling, serum Mg2+ level should be regularly monitored to prevent potentially fatal complications
Summary
The MAPK cascade is a signal transduction common to several cell types, and it is involved in many biological processes, including cell proliferation, differentiation, development, and apoptosis [1]. MAPK signalling is activated by a wide range of stimuli in mature kidney; these pathways have been shown to be critical in mediating cell response to different types of stress and injuries and to play a role in the pathophysiology of several diseases. Ko and coworkers demonstrated that ERK1,2 signalling mediates NCC regulation by phorbol esters (PE) or functional analogs [51] In their experiments, PE treatment decreased NCC surface expression through the stimulation of Ras guanyl-releasing protein 1 (RasGRP1)/Raf/MEK1,2 signalling. Additional studies demonstrated that PTH induces ERK2 phosphorylation in both PT and DCT cells, but ERK1,2 inhibition blocks the enhanced PTH-dependent Ca+2 entry in mDCT only [55] Both cell surface and total NCC expression are inhibited by the serine/threonine with no lysine kinase WNK4, via ERK1,2 signalling. The involvement of ERK 1,2 in the regulation of Na+ and K+ transport by PCs will be discussed
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