Tubuloglomerular feedback in ACE-deficient mice

In these experiments, we used a strain of angiotensin converting enzyme (ACE) germline null mutant mice, generated by J. H. Krege and co-workers (J. H. Krege, S. W. M. John, L. L. Langenbach, J. B. Hodgin, J. R. Hagaman, E. S. Bachman, J. C. Jennette, D. A. O’Brien, and O. Smithies. Nature 375: 146–148, 1995), to examine the effect of chronic ACE deficiency on the magnitude of tubuloglomerular feedback (TGF) responses. The genotype was determined by PCR on DNA extracted from the tail and was verified after each experiment by assessment of the blood pressure response to an injection of ANG I. To assess TGF responsiveness, we determined the change in stop-flow pressure (PSF) caused by increasing NaCl concentration at the macula densa by using micropuncture techniques. When loop of Henle flow rate was increased from 0 to 40 nl/min, PSF fell from a mean of 42.3 ± 1.95 to 33.6 ± 2.09 mmHg ( n = 6, P = 0.005) in wild-type mice (+/+), fell from 40.6 ± 2.35 to 38.6 ± 1.93 mmHg in heterozygous (+/−) mice ( n = 7, P = 0.014), and did not change in homozygous ACE (−/−) mice [36.7 ± 2.02 mmHg vs. 36.4 ± 2.01 mmHg; n = 4, P = not significant (NS)]. During an infusion of ANG II at a dose that did not significantly elevate blood pressure (70 ng ⋅ kg−1 ⋅ min−1), TGF response magnitude (PSF 0 − PSF 40) increased from 6.5 ± 1.4 to 9.8 ± 1.19 mmHg in +/+ ( P = 0.006), from 1.14 ± 0.42 to 4.6 ± 1.3 mmHg in +/− ( P = 0.016), and from 0.42 ± 0.25 to 4.02 ± 1.06 in −/− mice ( P = 0.05). Absence of TGF responses in ACE null mutant mice and restoration of near-normal responses during an acute infusion of ANG II supports previous conclusions that ANG II is an essential component in the signal transmission pathway that links the macula densa with the glomerular vascular pole.

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Role of nNOS in Blood Pressure Regulation in eNOS Null Mutant Mice

Hypertension ◽

10.1161/01.hyp.32.5.856 ◽

1998 ◽

Vol 32 (5) ◽

pp. 856-861 ◽

Cited By ~ 67

Author(s):

Nobutaka Kurihara ◽

Marcos E. Alfie ◽

David H. Sigmon ◽

Nour-Eddine Rhaleb ◽

Edward G. Shesely ◽

...

Keyword(s):

Blood Pressure ◽

Blood Pressure Regulation ◽

Mutant Mice ◽

Pressure Regulation ◽

Null Mutant ◽

Null Mutant Mice

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Renal cortical and medullary blood flow responses to l-NAME and ANG II in wild-type, nNOS null mutant, and eNOS null mutant mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00207.2005 ◽

2005 ◽

Vol 289 (4) ◽

pp. R991-R997 ◽

Cited By ~ 34

Author(s):

David L. Mattson ◽

Carla J. Meister

Keyword(s):

Blood Pressure ◽

Blood Flow ◽

Renal Cortex ◽

Renal Medulla ◽

Ang Ii ◽

Null Mutant ◽

Wild Type ◽

Medullary Blood Flow ◽

Arterial Blood ◽

Null Mutant Mice

Experiments in wild-type (WT; C57BL/6J) mice, endothelial nitric oxide synthase null mutant [eNOS(-/-)] mice, and neuronal NOS null mutant [nNOS(-/-)] mice were performed to determine which NOS isoform regulates renal cortical and medullary blood flow under basal conditions and during the infusion of ANG II. Inhibition of NOS with Nω-nitro-l-arginine methyl ester (l-NAME; 50 mg/kg iv) in Inactin-anesthetized WT and nNOS(-/-) mice increased arterial blood pressure by 28–31 mmHg and significantly decreased blood flow in the renal cortex (18–24%) and the renal medulla (13–18%). In contrast, blood pressure and renal cortical and medullary blood flow were unaltered after l-NAME administration to eNOS(-/-) mice, indicating that NO derived from eNOS regulates baseline vascular resistance in mice. In subsequent experiments, intravenous ANG II (20 ng·kg−1·min−1) significantly decreased renal cortical blood flow (by 15–25%) in WT, eNOS(-/-), nNOS(-/-), and WT mice treated with l-NAME. The infusion of ANG II, however, led to a significant increase in medullary blood flow (12–15%) in WT and eNOS(-/-) mice. The increase in medullary blood flow following ANG II infusion was not observed in nNOS(-/-) mice, in WT or eNOS(-/-) mice pretreated with l-NAME, or in WT mice administered the nNOS inhibitor 5-(1-imino-3-butenyl)-l-ornithine (1 mg·kg−1·h−1). These data demonstrate that NO from eNOS regulates baseline blood flow in the mouse renal cortex and medulla, while NO produced by nNOS mediates an increase in medullary blood flow in response to ANG II.

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00976.2006 ◽

2007 ◽

Vol 292 (4) ◽

pp. H1685-H1689 ◽

Cited By ~ 15

Author(s):

Pouneh Nouri ◽

Pritmohinder Gill ◽

Min Li ◽

Christopher S. Wilcox ◽

William J. Welch

Keyword(s):

Angiotensin Ii ◽

Nadph Oxidase ◽

Blood Pressure Response ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Distal Tubule ◽

Macula Densa ◽

Tubuloglomerular Feedback ◽

Ang Ii ◽

Renal Vasoconstriction ◽

Single Nephron

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 p22 phox 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 p22 phox to test the hypothesis that p22 phox 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 p22 phox and NADPH oxidase regulate the SNGFR during ANG II infusion via MD-dependent mechanisms.

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Angiotensin II directly stimulates macula densa Na-2Cl-K cotransport via apical AT1 receptors

AJP Renal Physiology ◽

10.1152/ajprenal.00129.2001 ◽

2002 ◽

Vol 282 (2) ◽

pp. F301-F306 ◽

Cited By ~ 38

Author(s):

Gergely Kovács ◽

János Peti-Peterdi ◽

László Rosivall ◽

P. Darwin Bell

Keyword(s):

Angiotensin Ii ◽

Fluorescence Microscopy ◽

Initial Rate ◽

Macula Densa ◽

Tubuloglomerular Feedback ◽

Ang Ii ◽

At1 Receptors ◽

Twofold Increase ◽

Nacl Concentration ◽

Sodium Binding

ANG II is a modulator of tubuloglomerular feedback (TGF); however, the site of its action remains unknown. Macula densa (MD) cells sense changes in luminal NaCl concentration ([NaCl]L) via a Na-2Cl-K cotransporter, and these cells do possess ANG II receptors. We tested whether ANG II regulates Na-2Cl-K cotransport in MD cells. MD cell Na+ concentration ([Na+]i) was measured using sodium-binding benzofuran isophthalate with fluorescence microscopy. Resting [Na+]i in MD cells was 27.7 ± 1.05 mM ( n = 138) and increased (Δ[Na+]i) by 18.5 ± 1.14 mM ( n = 17) at an initial rate (Δ[Na+]i/Δ t) of 5.54 ± 0.53 × 10−4 U/s with an increase in [NaCl]L from 25 to 150 mM. Both Δ[Na+]i and Δ[Na+]i/Δ t were inhibited by 80% with 100 μM luminal furosemide. ANG II (10−9 or 10−12 M) added to the lumen increased MD resting [Na+]i and [NaCl]L-dependent Δ[Na+]i and caused a twofold increase in Δ[Na+]i/Δ t. Bath (10−9 M) ANG II also stimulated cotransport activity, and there was no additive effect of simultaneous addition of ANG II to bath and lumen. The effects of luminal ANG II were furosemide sensitive and abolished by the AT1 receptor blocker candesartan. ANG II at 10−6 M failed to stimulate the cotransporter, whereas increased cotransport activity could be restored by blocking AT2 receptors with PD-123, 319. Thus ANG II may modulate TGF responses via alterations in MD Na-2Cl-K cotransport activity.

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