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. 2013 Jun;24(7):1053-62.
doi: 10.1681/ASN.2012080839. Epub 2013 Apr 18.

Deficiency of renal cortical EGF increases ENaC activity and contributes to salt-sensitive hypertension

Tengis S Pavlov  1 , Vladislav Levchenko, Paul M O'Connor, Daria V Ilatovskaya, Oleg Palygin, Takefumi Mori, David L Mattson, Andrey Sorokin, Julian H Lombard, Allen W Cowley Jr, Alexander Staruschenko
Affiliations

Deficiency of renal cortical EGF increases ENaC activity and contributes to salt-sensitive hypertension

Tengis S Pavlov et al. J Am Soc Nephrol. 2013 Jun.

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 low-salt 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.

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Figures

Figure 1.
Figure 1.
ENaC plays a significant role in the development of salt-sensitive hypertension. Effect of benzamil (15 mg/L, given through drinking water) on the MAP in SS rats fed a HS (4%) diet (n=5 rats in each group). *P<0.05 versus SS rats fed a HS treated with vehicle.
Figure 2.
Figure 2.
ENaC expression and activity are inappropriately upregulated in SS rats fed a HS diet. (A and B) Effects of a HS diet (4%, 3 weeks) on protein expression of ENaC subunits in the SS rats kidney cortex (n=7 in each group). The densitometry values are normalized to GAPDH. Equal loading control (GAPDH) is shown for analysis of α-ENaC expression. Similar equal loading control is done for analysis of β- and γ-ENaC subunits (not shown). (C and D) Western blots and summary graphs demonstrating expression of α-, β-, and γ-ENaC subunits in SS.13BN rats fed a LS or HS diet (n=4 in each group), respectively (0.4 and 4%, 3 weeks). Equal loading control (β-actin) is shown for analysis of α-ENaC expression. Similar equal loading control is done for analysis of β- and γ-ENaC subunits (not shown). GAPDH, Glyceraldehyde 3-phosphate dehydrogenase. ***P<0.001 versus LS diet.
Figure 3.
Figure 3.
Expression of β-ENaC in SS and consomic SS.13BN rats fed a HS diet. (A) Immunohistochemical staining and (B) summary graph of β-ENaC expression in the kidney cortex of SS and SS.13BN rats fed a HS diet (8%, 1 week). ***P<0.001 versus SS rats fed a HS diet. Original magnification, ×40 in A.
Figure 4.
Figure 4.
SS rats demonstrate higher ENaC activity on a HS diet compared with a LS diet and SS.13BN consomic rats. Representative single-channel traces (A) and summary graph (B) for ENaC from freshly isolated split opened CNTs/CCDs from SS and SS.13BN rats fed a LS or HS diet, respectively. These patches were held at the test potential of Vh = −Vp = −60 mV. Inward Li+ currents are downward. Dashed lines indicate the respective current state, with “c” and “on” denoting the closed and open states. *P<0.05 versus other groups.
Figure 5.
Figure 5.
Chronically elevated RPP alters ENaC expression and glomerular injury. (A) Representative immunohistochemical staining for β-ENaC (shown in brown) in SS rat kidney cortical sections of servo-controlled and uncontrolled kidneys. Negative control tissue stained with secondary antibodies in the absence of primary antibodies is also shown. (B) Schematic diagram of servo-control experiments. (C) Densitometric analysis of relative β-ENaC expression in the cortex of servo-controlled and uncontrolled kidneys harvested from SS rats fed a HS diet. (D) Representative images of glomeruli in Trichrome-stained left and right kidneys. (E) Average glomerular injury score calculated in the kidneys of experimental animals (n=6). *P<0.05 and **P<0.01 versus servo-controlled kidneys (n=6). Original magnification, ×40 in A and D.
Figure 6.
Figure 6.
EGF concentration in the kidney cortex isolated from SS and SS.13BN rats fed a LS or HS diet measured with ELISA assay. ***P<0.001 versus SS rats fed a LS diet and SS.13BN rats on both diets.
Figure 7.
Figure 7.
EGF decreases ENaC activity in SS rats fed a HS diet. Effect of intravenous infusion (3 days; 10 µg/h per kilogram) of EGF on the ENaC activity in SS rats fed a HS (4%) diet. SS rats are fed with a HS diet for 3 days before and during EGF treatment. Representative single-channel traces (A) and summary graph (B) for ENaC activity from freshly isolated split opened CNTs/CCDs derived from SS rats after the treatment with EGF or vehicle are shown. ***P<0.001 versus SS rats treated with vehicle.
Figure 8.
Figure 8.
Chronic intravenous infusion of EGF prevents development of hypertension and kidney damage in SS rats fed a HS diet. Protocol (A) and effect of intravenous EGF infusion on the MAP (B) in the SS rats fed a HS diet as described in the corresponding protocol (n=3–4). (C) Light microscopy of Trichrome-stained sections of whole kidney (×1) and renal cortex (×60) of SS rats fed a HS diet for 10 days and intravenously infused with vehicle or EGF (2 μg/h). The averaged percentage of protein casts area in the renal outer medulla (D) and the glomerular injury score (E) are shown. *P<0.05, **P<0.01, and ***P<0.001 versus SS rats treated with vehicle.
Figure 9.
Figure 9.
Effect of EGF infusion on urine and serum Na+ and K+ levels in SS rats fed a HS diet. (A) Na+ urinary concentrations normalized to creatinine in the vehicle- and EGF-treated groups before (day 0) and after (day 4, day 10) the HS diet started. (B and C) Na+ and K+ levels in serum remain unchanged during the experiment in both groups. n=4 in each group. §P<0.05 compared with day 0; *P<0.05 compared with saline, day 10.
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