Epidermal growth factor deficiency predisposes to progressive renal disease.

Epidermal growth factor (EGF) is produced in the kidney by thick ascending limbs of the loop of Henle and by distal convoluted tubules (DCTs). Reduced urinary EGF levels have been associated with chronic kidney disease but it is not known whether physiological levels of EGF protect the kidney from progressive renal disease. Here, we show that EGF-deficient mice on a mixed genetic background had increased urinary microalbumin, and a subset of these mice developed severe progressive renal disease with azotemia that was not seen in WT or TGFα-deficient littermates with this mixed genetic background. These azotemic EGF-deficient mice developed crescentic glomerulonephritis linked to HB-EGF/EGFR hyperactivation in glomeruli, as well as attenuation of the proximal tubule brush border, distal convoluted tubule (DCT) dilatation, and kidney fibrosis associated with renal ß-catenin/mTOR hyperactivation. The observation of these severe renal pathologies only in a subset of EGF-deficient mice suggests that independent segregation of strain-specific modifier alleles contributes to the severity of the renal abnormalities that only manifest when EGF is lacking. These findings link the lack of EGF to renal pathologies in the adult mammalian kidney, in support of a role of physiological levels of EGF for maintaining the function of glomeruli, proximal tubules, and DCTs. These observations suggest that diminished EGF levels predispose kidneys to progressive renal disease.

Transcription factors AP-2α and AP-2ß regulate distinct segments of the distal nephron in the mammalian kidney.

Transcription factors AP-2α and AP-2ß have been suggested to regulate the differentiation of nephron precursor populations towards distal nephron segments. Here, we show that in the adult mammalian kidney AP-2α is found in medullary collecting ducts, whereas AP-2ß is found in distal nephron segments except for medullary collecting ducts. Inactivation of AP-2α in nephron progenitor cells does not affect mammalian nephrogenesis, whereas its inactivation in collecting ducts leads to defects in medullary collecting ducts in the adult. Heterozygosity for AP-2ß in nephron progenitor cells leads to progressive distal convoluted tubule abnormalities and ß-catenin/mTOR hyperactivation that is associated with renal fibrosis and cysts. Complete loss of AP-2ß in nephron progenitor cells caused an absence of distal convoluted tubules, renal cysts, and fibrosis with ß-catenin/mTOR hyperactivation, and early postnatal death. Thus, AP-2α and AP-2ß have non-redundant distinct spatiotemporal functions in separate segments of the distal nephron in the mammalian kidney.