Enhanced oxidative stress in kidneys of salt-sensitive hypertension: role of sensory nerves

Abstract

To determine the mechanism(s) underlying enhanced oxidative stress in kidneys of salt-sensitive hypertension, neonatal Wistar rats were given vehicle or capsaicin (CAP, 50 mg/kg sc) on the first and second days of life. After being weaned, male rats were assigned into four groups and treated for 2 wk with the following: vehicle + a normal sodium diet (NS, 0.4%, CON-NS), vehicle + a high-sodium diet (HS, 4%, CON-HS), CAP + NS (CAP-NS), and CAP + HS (CAP-HS). Systolic blood pressure was significantly increased in CAP-HS but not CAP-NS or CON-HS rats. Plasma and urinary 8-iso-prostaglandin F(2alpha) levels increased by approximately 40% in CON-HS and CAP-HS rats compared with their respective controls fed a NS diet (P < 0.05), and these parameters were higher in CAP-HS compared with CON-HS rats. Superoxide (O(2)(-)*) levels in the renal cortex and medulla increased by approximately 45% in CAP-HS compared with CON-HS, CON-NS, and CAP-NS rats (P < 0.05). Enhanced O(2)(-)* levels in the cortex and medulla in CAP-HS rats were prevented by preincubation of renal tissues with apocynin, a selective NAD(P)H oxidase inhibitor. Protein expression of NAD(P)H oxidase subunits, including p47(phox) and gp91(phox) in the renal cortex and medulla, was significantly increased in CAP-HS compared with CON-HS, CON-NS, and CAP-NS rats. In contrast, protein expression and activities of Cu/Zn SOD and Mn SOD were significantly increased in the renal medulla in both CAP-HS and CON-HS but in the cortex in CAP-HS rats only. Creatinine clearance decreased by approximately 45% in CAP-HS rats compared with CON-HS, CON-NS, and CAP-NS rats (P< 0.05). O(2)(-)* levels in the renal cortex of CAP-HS rats negatively correlated with creatinine clearance (r = -0.76; P < 0.001). Therefore, regardless of enhanced SOD activity to suppress oxidative stress, increased oxidative stress in the kidney of CAP-treated rats fed a HS diet is likely the result of increased expression and activities of NAD(P)H oxidase, which may contribute to decreased renal function and increased blood pressure in these rats. Our results suggest that sensory nerves may play a compensatory role in attenuating renal oxidative stress during HS intake.

Fosinopril and Losartan Regulate Klotho Gene and Nicotinamide Adenine Dinucleotide Phosphate Oxidase Expression in Kidneys of Spontaneously Hypertensive Rats

“…Because of the important relationship between Klotho gene and oxidative stress, we have focused on renal oxidative stress in SHR. Renal oxidative stress has been detected in several hypertension models [21,22] . Experimental studies have established a role for oxidative stress in hypertensive renal damage and the therapeutic potential of antioxidant treatment [23,24] .…”

Enhanced salt sensitivity following shRNA silencing of neuronal TRPV1 in rat spinal cord

“…These data show that selective knockdown of neuronal TRPV1 enhances prohypertensive effects induced by salt loading and that pressor effects of TRPV1 shRNA may be mediated, at least in part, by enhancement of the sympatho-excitatory response. We have previously shown that neonatal degeneration of TRPV1-expressing sensory nerves increased salt sensitivity of arterial pressure as these rats grew into adulthood [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] . However, the systemic sensory denervation used in these previous studies precluded us from making conclusions about whether the observed effect was due to the removal of TRPV1 or other proteins co-expressed in the same nerves innervating any specific organs or tissues [21,22] .…”

“…Thus, defining the role of TRPV1-positive sensory nerves in the regulation of blood pressure and salt sensitivity will be useful. We have shown previously that the degeneration of TRPV1-expressing sensory nerves throughout the neonatal body by subcutaneous injection of capsaicin, a selective TRPV1 agonist, leads to increased salt sensitivity of arterial pressure, indicating that TRPV1-positive sensory nerves play a counter-regulatory role against salt-induced increases in blood pressure [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] . The underlying mechanism of anti-hypertensive effects of TRPV1 may involve its counter-balancing role against the activation of the renin-angiotensin-aldosterone system [7][8][9] , sympathetic nervous system [10] , endothelin system [11,12] , superoxide generation system [13,14] , and epithelial sodium transporters [15] .…”

Do distinct populations of dorsal root ganglion neurons account for the sensory peptidergic innervation of the kidney?

“…In a recent study, renal afferent innervation was linked to the amelioration of the consequences of oxidative stress (38). In rats with destruction of afferent sensory nerves due to early postnatal capsaicin treatment, enhanced O 2 Ϫ could be measured in the cortex and medulla of the kidney if these animals were on a high-salt diet.…”