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Am J Physiol Heart Circ Physiol 292: H1685-H1689, 2007. First published January 12, 2007; doi:10.1152/ajpheart.00976.2006
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Cardiovascular-Renal Mechanisms in Health and Disease

p22phox in the macula densa regulates single nephron GFR during angiotensin II infusion in rats

Pouneh Nouri, Pritmohinder Gill, Min Li, Christopher S. Wilcox, and William J. Welch

Department of Medicine, Georgetown University, Washington, District of Columbia

Submitted 7 September 2006 ; accepted in final form 21 December 2006


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Angiotensin II (ANG II) infusion increases renal superoxide (O2–) and enhances renal vasoconstriction via macula densa (MD) regulation of tubuloglomerular feedback, but the mechanism is unclear. We targeted the p22phox subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) with small-interfering RNA (siRNA) to reduce NADPH oxidase activity and blood pressure response to ANG II in rats. We compared single nephron glomerular filtration rate (SNGFR) in samples collected from the proximal tubule (PT), which interrupts delivery to the MD, and from the distal tubule (DT), which maintains delivery to the MD, to assess MD regulation of GFR. SNGFR was measured in control and ANG II-infused rats (200 ng·kg–1·min–1 for 7 days) 2 days after intravenous injection of vehicle or siRNA directed to p22phox to test the hypothesis that p22phox mediates MD regulation of SNGFR during ANG II. The regulation of SNGFR by MD, determined by PT SNGFR-DT SNGFR, was not altered by siRNA in control rats (control + vehicle, 13 ± 1, n = 8; control + siRNA, 12 ± 2 nl/min, n = 8; not significant) but was reduced by siRNA in ANG II-treated rats (ANG II + vehicle, 13 ± 2, n = 7; ANG II + siRNA, 7 ± 1 nl/min, n = 8; P < 0.05). We conclude that p22phox and NADPH oxidase regulate the SNGFR during ANG II infusion via MD-dependent mechanisms.

renal function; oxidative stress; hypertension; tubuloglomerular feedback; glomerular filtration rate

SUPEROXIDE (O2–) is produced in mitochondria and by cytosolic oxidases, such as xanthine oxidase; however, the major source in the kidney is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) (36). Vascular and renal O2– and NADPH oxidase activity is increased by angiotensin II (ANG II) acting on type 1 (AT1) receptors (7). Hypertension during ANG II is ameliorated by inhibition of NOX or by scavenging O2–, suggesting a role of NADPH oxidase in vascular function. O2– bioinactivates nitric oxide (NO). This generates peroxynitrite (ONOO–), thereby simultaneously reducing the powerful vasodilation mediated by NO and creating an oxidative and nitrosative agent. NO is formed in the macula densa (MD) by NO synthase, type 1 (NOS-1) (2, 15, 33), and modulates the tone of the afferent arteriole during stimulation of tubuloglomerular feedback (TGF), which is primarily a system that vasconstricts the renal afferent arteriole (14, 31, 32). Therefore, during ANG II-induced vasoconstriction, NOX activity is stimulated and could enhance MD-induced afferent arteriole resistance.1

We tested the hypothesis that increased NOX activity mediated by enhanced RNA expression for p22phox increases the role of the MD in reducing the single nephron glomerular filtration rate (SNGFR) in rats infused for 7 days with a subpressor dose of ANG II. This was assessed from a comparison of SNGFR values from samples drawn from the proximal tubule (PT) and from the distal tubule (DT). The difference in SNGFR derived from these two sites is a function of the influence of the MD on the GFR. The role for p22phox was assessed by the intravenous injection of small interfering RNA (siRNA) to p22phox subunit (compared with a scrambled sequence), which we have shown previously prevents the increase in p22phox RNA and protein in the rat kidney during ANG II infusion (14).


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Experimental design. Studies were approved by the Georgetown University Animal Care and Use Committee. Experiments were conducted in 31 male Sprague-Dawley rats, 8–10 wk of age and weighing 253–399 g. Two groups were used to study the role of p22phox under normal conditions (control). An osmotic minipump (model 2002, Alzet) delivering vehicle (0.9% NaCl) was placed in the nape of the neck under brief anesthesia (10 min) with 2% isoflurane on day 1, followed on day 5 by an injection of either vehicle (0.9% NaCl solution, n = 8) or siRNA to p22phox (n = 8). We previously injected siRNA one or two times via indwelling catheters (14); however, in this single-dose study, we injected the construct into the right jugular vein using the same hydrodynamic technique (7 ml over 10 s) under isoflurane anesthesia. Micropuncture was performed on day 7 for the measurement of the proximal and distal tubule SNGFR. Two other groups of rats were used to study the role of p22phox under conditions of oxidative stress induced by ANG II infusion. These rats received a slow pressor infusion of ANG II (200 ng·kg–1·min–1; Bachem, Torrance, CA) by an osmotic minipump for 7 days. They also received intravenous injections of either vehicle (n = 7) or siRNA to p22phox (n = 8) on day 5, under isoflurane anesthesia, and underwent micropuncture on day 7.

siRNA construction and injection. The siRNA construct was identical to the method previously described (14). Briefly, we transfected p22phox siRNA, scrambled RNA duplexes, or vehicle in A-10 aortic vascular smooth muscle cells (ATCC, Manassas, VA) using Lipofectamine 2000 (Invitrogen Life Technologies, Gaithersburg, MD). One hundred picomoles of p22phox siRNA reduced p22phox mRNA expression by 85%. The p22phox gene expression was assayed by TaqMan assay (Rn00577357_m1; ABI, Foster City, CA) using real-time PCR cycler 7700 (Applied Biosystems, Foster City, CA). For in vivo studies, the TransIT in vivo gene delivery system (Mirus, Madison, WI) was used.

Animal preparation and micropuncture studies. The animals were maintained with ad libitum access to tap water and normal rat chow (Na+ content, 0.3 g/100 g). Rats were anesthetized with Inactin (50 mg/kg body wt ip; Research Biochemicals), placed on a temperature-regulated micropuncture table, and given a tracheostomy for unventilated breathing and cannulation of the left jugular vein, right femoral artery, and bladder. The left kidney was exposed with a flank incision, cleared of perirenal tissue, and placed in a Lucite cup for micropuncture, as described in detail previously (32). The left jugular vein was cannulated with a polyethylene (PE)-50 catheter for 1% bovine serum albumin (Sigma) infusion during the surgical preparation at a rate of 1.0 ml·100 g–1·h–1. A PE-10 catheter was also inserted in the left jugular vein for bolus injections of 1% Lissamine green (Sigma) to identify distal tubules before samples from the DT were collected. After 30 min of equilibration, a 25-µCi bolus injection of [3H]inulin (ARC, St. Louis, MO) was given, followed by infusion of [3H]inulin (75 µCi/h) added to the maintenance infusion. Surface segments of PTs were identified and blocked distally by intratubular injection of 2% Sudan Black B in light mineral oil with a micropipette (8–10 µm OD). Three to six timed PT free-flow collections were obtained from different nephrons in each rat to determine the PT SNGFR. Since the flow to DT was blocked during PT fluid collection, the MD and thus TGF were not contributing to the control of the calculated PT SNGFR. DTs were mapped immediately thereafter by intravenous bolus injection of 0.2–0.5 ml of Lissamine green. Early DTs were identified, and three to six timed DT free-flow collections were obtained to determine the DT SNGFR. Since the flow to the DT and MD was intact during these collections, it was assumed that the MD and thus TGF were contributing to the control of the calculated DT SNGFR. Therefore, the difference in these two values represents the influence of the MD on SNGFR. Whereas this method does not identify the maximal TGF control via the MD, it clearly defines the role of the MD under ambient, free-flow assessment of SNGFR (20). At the end of the experiment, the left kidney was harvested and the cortex dissected and frozen for subsequent analysis of mRNA.

Tubular fluid volumes were determined by the transfer of collected samples to a constant bore capillary tube and used for computing the respective tubular fluid flow. Timed urine samples were collected in preweighed containers, and periodic plasma samples were obtained from femoral artery for [3H]inulin concentration. The [3H]inulin content of all tubular fluid, plasma and urine samples was determined by a scintillation counter (LS 6500 model, Beckman Instruments, Fullerton, CA). GFR for both single nephrons and whole kidneys was determined as the product of tubular fluid or urine flow and the ratio of tubular fluid inulin to plasma inulin, respectively. The tubular fluid-to-plasma inulin ratio was in the range of 1–3.4 for PT and 3.6–9 for DT. The regulation of SNGFR by MD was determined by the difference between PT SNGFR and DT SNGFR.

Data analysis. All data are presented as means ± SE. We used 2 x 2 group analysis of variance with Student's t-test for post hoc comparison of the subgroups. P < 0.05 was considered significant.


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Mean arterial pressure (MAP), GFR, and urine flow, measured under anesthesia, are presented in Table 1. MAP was higher in both ANG II-infused groups compared with controls. Urine flow was lower in ANG II rats compared with control-vehicle-treated rats, and siRNA normalized urine flow in ANG II rats. (Table 1). Whole kidney GFR, corrected for the body weight, was higher in siRNA-treated groups.


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  		Table 1. Body weight, MAP, GFR, and urine flow in 4 groups

 
The PT SNGFR ranged between 50 and 60 nl/min and was not different among groups (Fig. 1A). However, the DT SNGFR was increased by siRNA in ANG II-infused rats but not by siRNA in control rats (control, 40.2 ± 1.8 vs. control + siRNA, 40.4 ± 2.8 nl/min, not significant; ANG II, 38.2 ± 2.1 vs. ANG II + siRNA, 48.0 ± 3.2 nl/min, P < 0.05) (Fig. 1B). The influence of the MD was assessed by the difference in SNGFR measured from the proximal and distal tubules (as described above). The difference between PT and DT SNGFR in control rats was 12.2 ± 1.6 nl/min, indicating a substantial role for the MD. This value was reduced by nearly 50% (6.7 ± 0.9 nl/min) in rats injected with siRNA to p22phox in ANG II rats (Fig. 2).


Figure 1
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  		Fig. 1. A: proximal tubule (PT) single nephron glomerular filtration rate (SNGFR) in vehicle and ANG II-infused rats. B: distal tubule (DT) SNGFR in vehicle and ANG II-infused rats. **P < 0.01 compared with ANG II control.

 

Figure 2
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  		Fig. 2. Tubuloglomerular feedback (TGF) measured by the difference between PT and DT SNGFR in control and ANG II-infused rats: effects of control or siRNA treatment. **P < 0.01 compared with ANG II-control.

 
ANG II-infused rats had threefold higher expression of p22phox mRNA in the renal cortex compared with control. Injection of siRNA reduced the expression of p22phox mRNA in the renal cortex by 52% in the control group and by 85% in the ANG II-infused group (Fig. 3).


Figure 3
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  		Fig. 3. Relative mRNA expression in renal cortex from control and ANG II-infused rats 48 h after injection with vehicle or siRNA to p22phox. beta, P < 0.001 compared with control-vehicle; ***P < 0.001 compared with vehicle.

 

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This study shows that MD-induced reduction in SNGFR measured in vivo is dependent on p22phox-induced, NOX-dependent O2– during the infusion of ANG II. In ANG II-infused rats, MD control of SNGFR was reduced by 50% in rats treated with siRNA to p22phox compared with vehicle. We have shown previously that the increase in MAP by more prolonged infusion of ANG II in this model is abrogated by siRNA reduction of p22phox (14), but the role of the renal NOX was not assessed specifically in that study. Here we implicate p22phox in the MD regulation of SNGFR during ANG II. This suggests that the NOX system can regulate MD-afferent arteriolar signaling or responsiveness in ANG II-infused rats.

TGF is a graded vasoconstriction of the renal afferent arteriole in response to increased delivery and reabsorption of NaCl at the MD cells. Adjustments in TGF permit the timely and efficient excretion of NaCl in response to changes in salt intake or blood pressure and contribute to autoregulation of the renal blood flow, glomerular capillary pressure, and SNGFR (1). TGF is assessed by in vivo isolation of a single nephron with controlled perfusion of the loop of Henle (32) or by measuring the difference between SNGFR calculated from PT and DT collections (20). The latter method has the advantage of using ambient flows to test the role of MD under normal conditions, whereas the former method measures the maximal TGF capacity during perfusion of artificial fluids. Both methods have been used to evaluate the role of the MD in control of GFR (33).

Wilcox et al. (34) and Mundel et al. (15) described substantial expression of the neuronal isoform of NOS (NOS-1) in the MD cells of rats. NO generated by NOS-1 in the MD during luminal NaCl reabsorption blunts the TGF response (32). Chabrashvili et al. (2) reported that MD cells in rats also express a complete complement of NADPH oxidase components, which provoked the hypothesis that the TGF response is regulated by an interaction between O2– and NO in the juxtaglomerular apparatus (JGA). Welch and colleagues (14, 31–33) showed that TGF responses were enhanced in the spontaneously hypertensive rat, a model of hypertension and oxidative stress, because of a failure of NOS-1-derived NO to blunt TGF. They ascribed this to a local bioinactivation of NO by O2– with the formation of ONOO–.

ANG II can enhance the responsiveness of the TGF (22) and constrict the renal afferent arteriole (28). ANG II administered acutely either by intravenous infusion (13, 21) or by peritubular capillary infusion (13) significantly enhances the afferent arteriolar response to increased NaCl delivery to the MD. TGF is absent in homozygous AT1A receptor-deficient (23) or angiotensin-converting enzyme-deficient mice (26). Acute blockade of ANG II receptors (10, 17, 25) or ANG II generation attenuates TGF, which can be partly restored by intravenous infusion of ANG II. (25, 27). TGF is also enhanced in augmented ANG II conditions, such as one-kidney, one-clip hypertensive rats (18), or in the nonclipped kidney of Goldblatt hypertensive rats (8). Collectively, these data suggest a modulatory role for ANG II in the signal transduction pathway that links the MD with the glomerular vascular pole. Why the MD regulation of SNGFR was not enhanced by ANG II infusion in these studies is not established. It may represent counterbalancing effects of ANG II infused at a relatively low dose for 7 days to enhance NO generation (and likely to blunt TGF) and to enhance O2– generation (and thereby to enhance TGF). This would set the stage for demonstrating a blunting of MD control of SNGFR after deletion of the drive to O2– generation by siRNA administration to the ANG II-infused rats, as observed in this study.

The finding that whole kidney GFR was increased by siRNA to p22phox in both control and ANG II-infused rats was not anticipated since PT-DT SNGFR was reduced only in the ANG II-infused group. This might be related to an MD-independent effect of NADPH oxidase on the renal afferent arteriole since there is some regulation of the renal afferent arteriole even in normal rats (35). Alternately, it may signify that the outer cortical nephrons sampled in this study were not fully representative of whole kidney function.

Similarly, the decrease in urine flow in the control group treated with siRNA is not clearly understood, since GFR was increased (Table 1). It is possible that more distal effects of inhibition of NADPH oxidase decreased solute uptake, similar to the effects seen in the thick ascending loop of Henle (11), resulting in greater urine flow. However, since this was not observed in ANG II-infused rats, it will require further study to interpret.

During the slow pressor response to ANG II, several studies have shown that changes in renal function contribute to the hypertension. The lumen of preglomerular, but not postglomerular, arterioles is reduced by low-dose ANG II, infused either systemically (4, 9, 24) or via the renal artery (1). Characterization of the determinants of SNGFR in the Munich- Wistar rats show a predominant increase in efferent arteriolar resistance with maintenance of filtration because an increase in glomerular capillary hydrostatic pressure is offset by a reduction in glomerular plasma flow and ultrafiltration coefficient (1).

ANG II stimulates renal NADP/NADPH oxidase (29) and thereby reduces NO bioactivity (34). Indeed, studies in the spontaneously hypertensive rat have concluded that inhibition of O2– by Tempol can restore NO signaling in the JGA (31). Guan et al. (6) reported that an acute intrarenal infusion of ANG II increases oxidant activity and facilitated autoregulation of renal blood flow by local depletion of NO. Suppression of the expression of p22phox was selected to study the role of NADPH oxidase activity, since it is apparently a requirement for the activity of the NOS-1, -2 and -4 isoforms of NADPH oxidase (5). O2– generated in the thick ascending limb of Henle may also affect NO-regulated Na+ uptake and thus alter the signal to the MD that initiates TGF (19). In addition, recent evidence suggests that O2– may increase TGF by direct constriction of the renal arterioles (12). The exact mechanism of O2– action on TGF is not established by this study.

Other evidence that the slow pressor ANG II model represents a balance between O2– and NO comes from the finding that N{omega}-nitro-L-arginine methyl ester (L-NAME) accelerates the increase in MAP to low-dose ANG II (3). This effect of L-NAME is maximal at 2–4 days. Conversely, low-dose infusion of ANG II increases excretion of isoprostanes, a marker for O2– production (16), and increases renal cortical NOX activity (14). We showed previously that a reduction of NOX by siRNA to p22phox ameliorated hypertension and excretion of isoprostane during ANG II infusion (14). The present study demonstrates important functional changes in the renal regulation of hemodynamics due to p22phox in this model.

Perspectives

NOX expression is increased by low doses of ANG II (2). Therefore, the reduction of NOX by siRNA to p22phox in ANG II-infused rats may explain the blunting of the role of the MD in regulation of SNGFR. The absence of an effect of siRNA to p22phox in normal rats is consistent with prior findings that oxidative stress in the JGA of normal rats has a minimal or absent effect on TGF and MD-afferent arteriolar signaling (32). A blunting of TGF by siRNA to p22phox in ANG II-infused rats may perhaps contribute to the reduction in blood pressure seen in conscious animals in our previous study. A fall in blood pressure was not seen in this study under anesthesia and at an earlier phase of ANG II infusion. These results link renal NOX to the control of GFR by the MD.


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This study was supported by National Heart, Lung, and Blood Institute Grant PO1-HL-68686-06.


   FOOTNOTES
 

Address for reprint requests and other correspondence: W. J. Welch, Dept. of Medicine, Georgetown Univ., 4000 Reservoir Road, Bldg. D-395, Washington, DC 20057 (e-mail: welchw{at}georgetown.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This paper was presented at the 9th Cardiovascular-Kidney Interactions in Health and Disease Meeting at Amelia Island Plantation, Florida, on May 26–29, 2006. Back


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