ABSTRACT
Kidney injury is a common complication of severe disease. Here, we report that injuries of the zebrafish embryonal kidney are rapidly repaired by a migratory response in 2-, but not in 1-day-old embryos. Gene expression profiles between these two developmental stages identify cxcl12a and myca as candidates involved in the repair process. Zebrafish embryos with cxcl12a, cxcr4b, or myca deficiency display repair abnormalities, confirming their role in response to injury. In mice with a kidney-specific knockout, Cxcl12 and Myc gene deletions suppress mitochondrial metabolism and glycolysis, and delay the recovery after ischemia/reperfusion injury. Probing these observations in zebrafish reveal that inhibition of glycolysis slows fast migrating cells and delays the repair after injury, but does not affect the slow cell movements during kidney development. Our findings demonstrate that Cxcl12 and Myc facilitate glycolysis to promote fast migratory responses during development and repair, and potentially also during tumor invasion and metastasis.
Subject(s)
Chemokine CXCL12/metabolism , Gene Expression Regulation, Developmental , Kidney Diseases/metabolism , Proto-Oncogene Proteins/metabolism , Zebrafish Proteins/metabolism , Zebrafish/genetics , Animals , Animals, Genetically Modified , Cell Movement , Energy Metabolism , Gene Deletion , Gene Expression Profiling , Glycolysis , Homeostasis , Kidney/injuries , Kidney/metabolism , Male , Mice , Mice, Inbred C57BL , Signal Transduction , Tretinoin/chemistryABSTRACT
Polycystic kidney disease (PKD) and other renal ciliopathies are characterized by cysts, inflammation, and fibrosis. Cilia function as signaling centers, but a molecular link to inflammation in the kidney has not been established. Here, we show that cilia in renal epithelia activate chemokine signaling to recruit inflammatory cells. We identify a complex of the ciliary kinase LKB1 and several ciliopathy-related proteins including NPHP1 and PKD1. At homeostasis, this ciliary module suppresses expression of the chemokine CCL2 in tubular epithelial cells. Deletion of LKB1 or PKD1 in mouse renal tubules elevates CCL2 expression in a cell-autonomous manner and results in peritubular accumulation of CCR2+ mononuclear phagocytes, promoting a ciliopathy phenotype. Our findings establish an epithelial organelle, the cilium, as a gatekeeper of tissue immune cell numbers. This represents an unexpected disease mechanism for renal ciliopathies and establishes a new model for how epithelial cells regulate immune cells to affect tissue homeostasis.
Subject(s)
Chemokine CCL2/metabolism , Cilia/pathology , Kidney Diseases, Cystic/congenital , Polycystic Kidney, Autosomal Dominant/pathology , Protein Kinase C/genetics , Protein Serine-Threonine Kinases/genetics , AMP-Activated Protein Kinases , Adaptor Proteins, Signal Transducing , Animals , Carrier Proteins/metabolism , Cell Line , Cytoskeletal Proteins , Dogs , Epithelial Cells/metabolism , Female , HEK293 Cells , Humans , Kidney Diseases, Cystic/pathology , Kidney Tubules/cytology , Kidney Tubules/pathology , Macrophages/metabolism , Madin Darby Canine Kidney Cells , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Phagocytosis/physiology , Polycystic Kidney, Autosomal Dominant/genetics , Protein Kinase C/metabolism , Protein Serine-Threonine Kinases/metabolism , ZebrafishABSTRACT
A dietary potassium load induces a rapid kaliuresis and natriuresis, which may occur even before plasma potassium and aldosterone (aldo) levels increase. Here we sought to gain insight into underlying molecular mechanisms contributing to this response. After gastric gavage of 2% potassium, the plasma potassium concentrations rose rapidly (0.25 h), followed by a significant rise of plasma aldo (0.5 h) in mice. Enhanced urinary potassium and sodium excretion was detectable as early as spot urines could be collected (about 0.5 h). The functional changes were accompanied by a rapid and sustained (0.25-6 h) dephosphorylation of the NaCl cotransporter (NCC) and a late (6 h) upregulation of proteolytically activated epithelial sodium channels. The rapid effects on NCC were independent from the coadministered anion. NCC dephosphorylation was also aldo-independent, as indicated by experiments in aldo-deficient mice. The observed urinary sodium loss relates to NCC, as it was markedly diminished in NCC-deficient mice. Thus, downregulation of NCC likely explains the natriuretic effect of an acute oral potassium load in mice. This may improve renal potassium excretion by increasing the amount of intraluminal sodium that can be exchanged against potassium in the aldo-sensitive distal nephron.
