Deficiency of Renal Cortical EGF Increases ENaC Activity and Contributes to Salt-Sensitive Hypertension

Abstract

Various stimuli, including hormones and growth factors, modulate epithelial sodium channels (ENaCs), which fine-tune Na + absorption in the kidney. Members of the EGF family are important for maintaining transepithelial Na + transport, but whether EGF influences ENaC, perhaps mediating salt-sensitive hypertension, is not well understood. Here, the ENaC inhibitor benzamil attenuated the development of hypertension in Dahl salt-sensitive rats. Feeding these salt-sensitive rats a high-salt diet led to lower levels of EGF in the kidney cortex and enhanced the expression and activity of ENaC compared with feeding a lowsalt diet. To directly evaluate the role of EGF in the development of hypertension and its effect on ENaC activity, we infused EGF intravenously while continuously monitoring BP of the salt-sensitive rats. Infusion of EGF decreased ENaC activity, prevented the development of hypertension, and attenuated glomerular and renal tubular damage. Taken together, these findings indicate that cortical EGF levels decrease with a high-salt diet in salt-sensitive rats, promoting ENaC-mediated Na + reabsorption in the collecting duct and the development of hypertension. More than 76 million American adults have high BP 1 and the likelihood of developing hypertension significantly increases with age. Nearly 40% of African Americans aged .20 years exhibit hypertension and nearly 70% of these individuals have a form of hypertension that is highly sensitive to salt intake. A reduced ability to maintain sodium homeostasis and normal levels of arterial pressure is a hallmark of all forms of hypertension. 2 In the kidney, discretionary Na + reabsorption in response to endocrine input to the aldosterone-sensitive distal nephron (ASDN) is a determinant of the pressurenatriuresis relationship, which is of fundamental importance in the long-term control of arterial pressure. 2,3 Although sodium transport in ASDN accounts for a small proportion of renal sodium transport (,10%), ENaC activity is the rate-limiting step for this discretionary Na + reabsorption. 4 The Dahl salt-sensitive (SS) rat strain used in this study is a genetic animal model of hypertension and kidney disease that reveals disease traits similar to those observed in humans. This inbred strain exhibits a low-renin, sodium-sensitive form of hypertension that is associated with severe and progressive proteinuria, glomerulosclerosis, and renal interstitial fibrosis. [5][6][7] The EGF and related hormones are multipotent agents [8][9][10][11] involved in regulation of various renal

Reactive oxygen species as important determinants of medullary flow, sodium excretion, and hypertension

“…Inhibition of ENaC by chronic administration of benzamil significantly reduced salt-induced hypertension in SS rats. It was also found that mRNA and protein expression of ENaC subunits was significantly increased in the renal cortex of the SS rats fed a high-salt diet (87,152). Since it was previously reported that ROS might be involved in the control of ENaC (47,81,190), these pathways may together act to amplify the development of salt-sensitive hypertension in SS rats.…”

“…The extent to which pathways identified with oxidative stress in the renal cortex are responsible for the progressive reduction of GFR in SS rats remains unclear and is currently being explored. Related to this is evidence that epithelial Na channel (ENaC)-mediated sodium absorption in the cortical collecting ducts is enhanced and contributes to hypertension in SS rats (152). Inhibition of ENaC by chronic administration of benzamil significantly reduced salt-induced hypertension in SS rats.…”

Antagonism of the prostaglandin E2 EP1 receptor in MDCK cells increases growth through activation of Akt and the epidermal growth factor receptor

“…For example, PGE 2 , produced in response to EGF in RPT cells, stimulates basolateral organic anion transport (47), while PGE 2 , produced in response to EGF in mesangial cells, causes decreased expression of cyclin D3, and hypertrophy (43). In addition to stimulating PGE 2 production, activation of the EGFR has other functional consequences, including inhibition of the epithelial sodium channel (ENaC) in the collecting duct, unlike PGE 2 which targets Na-K-ATPase in this nephron segment (40).…”

Implementing Patch Clamp and Live Fluorescence Microscopy to Monitor Functional Properties of Freshly Isolated PKD Epithelium

“…6. Use PCK or SD rat kidney central slices containing papilla for isolation of non-dilated CNT/CCDsegments [18][19][20][21] . NOTE: Papillary tissues are more durable than cortex and by holding papillary tubular bands with forceps and tearing along radial axis the slice can be cleaved into thin sectors.…”

“…Store gap-free single channel current data from gigaOhm seals for subsequent analysis. Analyze the channel events using a software package generally supplied with patch-clamp setups 18 . Calculate channel activity as NPo where N refers to the number of active channels in the patch and P o is average open probability of the channels.…”