Micropuncture determination of nephron function in mice without tissue angiotensin-converting enzyme

Hashimoto, Seiji; Adams, Jon W.; Bernstein, Kenneth E.; Schnermann, Jürgen

doi:10.1152/ajprenal.00297.2004

Cited by 42 publications

(45 citation statements)

References 37 publications

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“…Previous micropuncture studies showed that the absence of tissue-bound ACE blunts the tubuloglomerular feedback mechanism response. 32 In addition, our mice lack endothelial ACE, perhaps reducing angiotensin II availability in the renal vasculature. The second and more important consideration is that modulation of glomerular hemodynamics and/or GFR by renal ACE plays an important role in the initial hypertensive response to L-NAME.…”

Section: Discussionmentioning

confidence: 97%

Renal Angiotensin-Converting Enzyme Is Essential for the Hypertension Induced by Nitric Oxide Synthesis Inhibition

Giani

Janjulia

Kamat

et al. 2014

Journal of the American Society of Nephrology

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The kidney is an important source of angiotensin-converting enzyme (ACE) in many species, including humans. However, the specific effects of local ACE on renal function and, by extension, BP control are not completely understood. We previously showed that mice lacking renal ACE, are resistant to the hypertension induced by angiotensin II infusion. Here, we examined the responses of these mice to the low-systemic angiotensin II hypertensive model of nitric oxide synthesis inhibition with L-NAME. In contrast to wild-type mice, mice without renal ACE did not develop hypertension, had lower renal angiotensin II levels, and enhanced natriuresis in response to L-NAME. During L-NAME treatment, the absence of renal ACE was associated with blunted GFR responses; greater reductions in abundance of proximal tubule Na + /H + exchanger 3, Na + /Pi co-transporter 2, phosphorylated Na + /K + /Cl 2 cotransporter, and phosphorylated Na + /Cl 2 cotransporter; and greater reductions in abundance and processing of the g isoform of the epithelial Na + channel. In summary, the presence of ACE in renal tissue facilitates angiotensin II accumulation, GFR reductions, and changes in the expression levels and post-translational modification of sodium transporters that are obligatory for sodium retention and hypertension in response to nitric oxide synthesis inhibition.

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Section: Discussionmentioning

confidence: 97%

Renal Angiotensin-Converting Enzyme Is Essential for the Hypertension Induced by Nitric Oxide Synthesis Inhibition

Giani

Janjulia

Kamat

et al. 2014

Journal of the American Society of Nephrology

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“…32 To determine kidney GFR and nephron filtration and reabsorption rates, mice were infused with 125 I iothalamate (Glofil; Questcor Pharmaceuticals, Hayward, CA) at about 40 Ci/h. End proximal segments were identified by injecting a bolus of artificial tubular fluid stained with FD&C green from a 3-to 4-m tip pipette.…”

Section: Hemoglobin A1cmentioning

confidence: 99%

The Sweet Pee Model for Sglt2 Mutation

Onay

Sison

et al. 2011

Journal of the American Society of Nephrology

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Inhibiting renal glucose transport is a potential pharmacologic approach to treat diabetes. The renal tubular sodium-glucose transporter 2 (SGLT2) reabsorbs approximately 90% of the filtered glucose load. An animal model with sglt2 dysfunction could provide information regarding the potential long-term safety and efficacy of SGLT2 inhibitors, which are currently under clinical investigation. Here, we describe Sweet Pee, a mouse model that carries a nonsense mutation in the Slc5a2 gene, which results in the loss of sglt2 protein function. The phenotype of Sweet Pee mutants was remarkably similar to patients with mutations in the Scl5a2 gene. The Sweet Pee mutants had improved glucose tolerance, higher urinary excretion of calcium and magnesium, and growth retardation. Renal physiologic studies demonstrated a prominent distal osmotic diuresis without enhanced natriuresis. Sweet Pee mutants did not exhibit increased KIM-1 or NGAL, markers of acute tubular injury. After induction of diabetes, Sweet Pee mice had better overall glycemic control than wild-type control mice, but had a higher risk for infection and an increased mortality rate (70% in homozygous mutants versus 10% in controls at 20 weeks). In summary, the Sweet Pee model allows study of the long-term benefits and risks associated with inhibition of SGLT2 for the management of diabetes. Our model suggests that inhibiting SGLT2 may improve glucose control but may confer increased risks for infection, malnutrition, volume contraction, and mortality.

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“…From a recent study with differential genetic ablation of ACE in mice (17), it was concluded that local ANG II generation by renal tissue ACE is required for TGF. The massive TGF augmentation by pressure-dependent RAS changes observed in our experiments (Fig.…”

Section: Tubuloglomerular Feedback In Rbf Controlmentioning

confidence: 99%

The renin-angiotensin system and the third mechanism of renal blood flow autoregulation

Seeliger¹,

Wronski²,

Ladwig³

et al. 2009

American Journal of Physiology-Renal Physiology

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Seeliger E, Wronski T, Ladwig M, Dobrowolski L, Vogel T, Godes M, Persson PB, Flemming B. The renin-angiotensin system and the third mechanism of renal blood flow autoregulation. Am J Physiol Renal Physiol 296: F1334 -F1345, 2009. First published April 1, 2009 doi:10.1152/ajprenal.90476.2008.-Autoregulation of renal blood flow comprises three mechanisms: the myogenic response (MR), the tubuloglomerular feedback (TGF), and a third mechanism (3M). The nature of 3M is unknown; it may be related to hypotensive resetting of autoregulation that probably relies on pressure-dependent stimulation of the renin-angiotensin system (RAS). Thus we used a normotensive angiotensin II clamp in anesthetized rats and studied autoregulation 1) by slow ramp-shaped reductions in renal perfusion pressure (RPP) followed by ramp-shaped RPP restorations and 2) by means of the step response technique: after 30 s of either total or partial suprarenal aortic occlusion, a step increase in RPP was made and the response of renal vascular conductance analyzed to assess the mechanisms' strength and initial direction (vasodilation or constriction). The angiotensin clamp abolished the resetting of autoregulation during ramp-shaped RPP changes. Under control conditions, the initial TGF response was dilatory after total occlusions but constrictive after partial occlusions. The initial 3M response presented a mirror image to the TGF: it was constrictive after total but dilatory after partial occlusions. The angiotensin clamp suppressed the TGF and turned the initial 3M response following total occlusions into dilation. We conclude that 1) pressure-dependent RAS stimulation is a major cause behind hypotensive resetting of autoregulation, 2) TGF sensitivity strongly depends on pressure-dependent changes in RAS activity, 3) the 3M is modulated, but not mediated, by the RAS, and 4) the 3M acts as a counterbalance to the TGF and might possibly be related to the recently described connecting tubule glomerular feedback. renal hemodynamics; time domain; oscillations; hindquarter CHANGES IN PERFUSION PRESSURE alter local blood flow by a variety of mechanisms. On one hand, changes in pressure result in passive circular stretching or destretching of vessels and thus in parallel changes in blood flow. On the other hand, via various pathways, pressure changes evoke active responses of vascular smooth muscles, i.e., vasoconstriction or vasodilation. First, pressure-induced flow changes result in metabolic changes in the tissue that, in turn, impinge on vascular muscles, as exemplified by the phenomenon of reactive hyperemia (5, 6). Second, flow changes alter shear stress, which impacts on vascular muscles, e.g., via altered release of nitric oxide (8). Third, in many vascular beds the phenomenon of blood flow autoregulation is observed, i.e., the ability to dampen or even to abolish the effects that changes in perfusion pressure would otherwise inevitably have on flow (16,35).Compared with blood flow control of other vascular beds, control of renal blood flow (RB...

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Micropuncture determination of nephron function in mice without tissue angiotensin-converting enzyme

Abstract: . Micropuncture determination of nephron function in mice without tissue angiotensin-converting enzyme.

Cited by 42 publications

References 37 publications

Renal Angiotensin-Converting Enzyme Is Essential for the Hypertension Induced by Nitric Oxide Synthesis Inhibition

Renal Angiotensin-Converting Enzyme Is Essential for the Hypertension Induced by Nitric Oxide Synthesis Inhibition

The Sweet Pee Model for Sglt2 Mutation

The renin-angiotensin system and the third mechanism of renal blood flow autoregulation

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