Epidermal growth factor deficiency predisposes to progressive renal disease

Abstract

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 β‐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.

Aerobic Exercise Training Improves Renal Injury in Spontaneously Hypertensive Rats by Increasing Renalase Expression in Medulla

“…On the one hand, RNLS is an amine oxidase that regulates blood flow by metabolizing catecholamines and improves the injury caused by insufficient perfusion. In contrast, previous studies have shown that RNLS directly affects the function of renal tubular cells (49,50).…”

“…Renal tubules have the function of material transport, including reabsorption and secretion. Meanwhile, renal tubule epithelial cells can regulate renal function by secreting various factors ( 49 ). Our data suggested that the level of RNLS in DT and TAL was significantly increased after exercise, while the level of RNLS in renal tubular epithelial cells of cortex was lower than that of DT.…”

Urine Epidermal Growth Factor and Kidney Function Decline in Middle-Aged Adults

“… 30 A series of experimental studies have shown that EGF-deficient mice developed attenuation of the proximal tubular brush border and kidney fibrosis; in rats, EGF promotes kidney tubule cell regeneration, and it improves kidney function recovery after acute kidney injury. 30 , 31 , 32 In humans, kidney biopsy studies in patients with CKD have demonstrated that lower EGF mRNA expression correlates with greater tubulointerstitial injury, whereas higher urine EGF concentrations are indicative of functional kidney tubules and higher regeneration capability. 33 , 34 These findings, spanning from experimental animals to multiple human populations, directionally align with the results observed in this study.…”