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William T Noonan

Publications and source records attributed to William T Noonan.

6 recordsLinked to original sources
PubMed2004

Blood pressure maintenance in NHE3-deficient mice with transgenic expression of NHE3 in small intestine.

NHE3 Na(+)/H(+) exchanger knockout (Nhe3(-/-)) mice have severe absorptive deficits in the kidney proximal tubule and intestinal tract. The resulting hypovolemia has confounded efforts to carefully evaluate the specific effects of NHE3 deficiency on kidney function. Development of mice with transgenic expression of NHE3 in the small intestine (tgNhe3(-/-)) has allowed us to analyze the role of renal NHE3 in overall maintenance of blood pressure, pressure natriuresis, and autoregulation of both glomerular filtration rate (GFR) and renal blood flow (RBF). Ambulatory blood pressure, measured by telemetry, was lower in tgNhe3(-/-) mice than in wild-type controls (tgNhe3(+/+)) when the mice were maintained on a normal NaCl diet but was normalized when they were provided with a high NaCl intake. Furthermore, administration of the AT1-receptor blocker losartan showed that circulating ANG II plays a major role in maintaining blood pressure in tgNhe3(-/-) mice fed normal NaCl but not in those receiving high NaCl. Clearance studies revealed a blunted pressure-natriuresis response in tgNhe3(-/-) mice at lower blood pressures but a robust response at higher blood pressures. Autoregulation of GFR and RBF was normal in tgNhe3(-/-) mice. These results show that dietary NaCl loading normalizes blood pressure in awake tgNhe3(-/-) mice and that alterations in NHE3 activity are not essential for normal autoregulation of GFR and RBF. Furthermore, the data strongly support the hypothesis that NHE3 plays an important role in the diuretic and natriuretic responses to increases in blood pressure but also show that mechanisms not involving NHE3 mediate pressure natriuresis in the higher range of blood pressures studied.

Angiotensin II↗
PubMed2004

Development of late-stage diabetic nephropathy in OVE26 diabetic mice.

OVE26 mice are a transgenic model of severe early-onset type 1 diabetes. These mice develop diabetes within the first weeks of life and can survive well over a year with no insulin treatment, and they maintain near normal body weight. To determine whether OVE26 mice provide a valuable model of chronic diabetic nephropathy (DN), OVE26 diabetic mice were compared with their nondiabetic littermates for functional and structural characteristics of DN. OVE26 mice exhibited pronounced polyuria and significant albuminuria by 2 months of age (305 microg/24 h in OVE26 vs. 20 microg/24 h in controls). Albumin excretion rate increased progressively with age and exceeded 15,000 microg/24 h at 9 months of age. The profound loss of albumin led to hypoalbuminemia in some diabetic animals. Albuminuria coincided with an elevation in blood pressure as measured by tail cuff. The glomerular filtration rate (GFR) in OVE26 mice measured using fluorescein isothiocynate inulin clearance demonstrated that GFR increased significantly from 2 to 3 months of age and then decreased significantly from 5 to 9 months. GFR in 9-month-old diabetic mice was significantly lower than that of 9-month-old control mice. The decline in GFR coincided with a significant increase in renal vascular resistance. Structural studies showed an almost twofold increase in kidney weight between 2 and 5 months. Diabetic mice also showed progressively enlarged glomeruli and expanded mesangium with diffuse and nodular expansion of mesangial matrix. Tubulointerstitial fibrosis was also observed in these mice. Glomerular basement membrane was thickened in OVE26 mice. In summary, OVE26 mice demonstrate that most of the characteristics of human DN can be produced by chronic hyperglycemia in a murine model. This model will be useful for improved understanding and treatment of DN.

Aging↗
PubMed2003

Altered renal hemodynamics in mice overexpressing the parathyroid hormone (PTH)/PTH-related peptide type 1 receptor in smooth muscle.

PTH-related protein (PTHrP) is an autocrine/paracrine peptide expressed in renal tubules and vasculature and may play an important role in regulating overall renal function. To evaluate the potential role of endogenous PTHrP in the control of renal hemodynamics, we performed clearance measurements in transgenic (TG) mice in which the SMP8 alpha-actin promoter was used to drive overexpression of the PTH/PTHrP type 1 receptor in smooth muscle. In protocol I, responses to acute saline volume expansion (SVE, 0.75 microl/min.g body weight) were measured in TG and nontransgenic (NTG) mice. Mean arterial pressure was significantly lower in TG mice throughout the experiment, and it decreased comparably in both groups in response to SVE. SVE significantly increased effective renal plasma flow in both groups of mice, but the increase was greater in TG than in NTG. Glomerular filtration rate decreased in response to SVE in NTG but did not change in TG animals. In protocol II, renal responses to angiotensin II (ANG II) infusion were determined (0.5 ng/min.g body weight). Baseline arterial pressure was again significantly lower in TG, compared with NTG mice, and TG mice had a blunted pressor response to ANG II. Also, ANG II decreased effective renal plasma flow and glomerular filtration rate in both groups of animals, but the reductions were less in TG than in NTG mice. Our findings indicate that smooth-muscle-specific overexpression of the PTH/PTHrP type 1 receptor resulted in augmentation of the vasodilatory response to SVE and attenuation of the vasoconstrictor response to ANG II. We conclude that endogenous PTHrP can act as an endogenous vasorelaxant factor to modulate renal responses to vasoactive stimuli.

Actins↗
PubMed2003

Renal function in NHE3-deficient mice with transgenic rescue of small intestinal absorptive defect.

The degree to which loss of the NHE3 Na(+)/H(+) exchanger in the kidney contributes to impaired Na(+)-fluid volume homeostasis in NHE3-deficient (Nhe3(-/-)) mice is unclear because of the coexisting intestinal absorptive defect. To more accurately assess the renal effects of NHE3 ablation, we developed a mouse with transgenic expression of rat NHE3 in the intestine and crossed it with Nhe3(-/-) mice. Transgenic Nhe3(-/-) (tgNhe3(-/-)) mice tolerated dietary NaCl depletion better than nontransgenic knockouts and showed no evidence of renal salt wasting. Unlike nontransgenic Nhe3(-/-) mice, tgNhe3(-/-) mice tolerated a 5% NaCl diet. When fed a 5% NaCl diet, tgNhe3(-/-) mice had lower serum aldosterone than tgNhe3(-/-) mice on a 1% NaCl diet, indicating improved extracellular fluid volume status. Na(+)-loaded tgNhe3(-/-) mice had sharply increased urinary Na(+) excretion, reflective of increased absorption of Na(+) in the small intestine; nevertheless, they remained hypotensive, and renal studies showed a reduction in glomerular filtration rate (GFR) similar to that observed in nontransgenic Nhe3(-/-) mice. These data show that reduced GFR, rather than being secondary to systemic hypovolemia, is a major renal compensatory mechanism for the loss of NHE3 and indicate that loss of NHE3 in the kidney alters the set point for Na(+)-fluid volume homeostasis.

Aldosterone↗
PubMed2002

Impaired renal NaCl absorption in mice lacking the ROMK potassium channel, a model for type II Bartter's syndrome.

ROMK is an apical K(+) channel expressed in the thick ascending limb of Henle (TALH) and throughout the distal nephron of the kidney. Null mutations in the ROMK gene cause type II Bartter's syndrome, in which abnormalities of electrolyte, acid-base, and fluid-volume homeostasis occur because of defective NaCl reabsorption in the TALH. To understand better the pathogenesis of type II Bartter's syndrome, we developed a mouse lacking ROMK and examined its phenotype. Young null mutants had hydronephrosis, were severely dehydrated, and approximately 95% died before 3 weeks of age. ROMK-deficient mice that survived beyond weaning grew to adulthood; however, they had metabolic acidosis, elevated blood concentrations of Na(+) and Cl(-), reduced blood pressure, polydipsia, polyuria, and poor urinary concentrating ability. Whole kidney glomerular filtration rate was sharply reduced, apparently as a result of hydronephrosis, and fractional excretion of electrolytes was elevated. Micropuncture analysis revealed that the single nephron glomerular filtration rate was relatively normal, absorption of NaCl in the TALH was reduced but not eliminated, and tubuloglomerular feedback was severely impaired. These data show that the loss of ROMK in the mouse causes perturbations of electrolyte, acid-base, and fluid-volume homeostasis, reduced absorption of NaCl in the TALH, and impaired tubuloglomerular feedback.

Animals↗