Potential importance of glomerular citrate synthase activity in remnant nephropathy

Ullian, Michael E.; Gantt, Benjamin J.; Ford, Amy; Tholanikunnel, Baby G.; Spicer, Eleanor K.; Fitzgibbon, Wayne R.

doi:10.1046/j.1523-1755.2003.00731.x

Cited by 6 publications

(8 citation statements)

References 20 publications

(7 reference statements)

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“…Although mean arterial BP was 20 mmHg lower in Wistar-Furth rats than Wistar rats with 5/6 nephrectomy, albuminuria remained more than 10-fold higher in Wistar rats with 5/6 nephrectomy that had BP controlled to an equal level by a hydralazine-reserpinehydrochlorothiazide treatment regimen. Isolated glomeruli from Wistar-Furth rats, unlike Wistar rats, showed no increase in citrate synthase in response to direct application of aldosterone [6]. These findings further support the hypothesis that aldosterone itself has a role in mediating progressive renal disease through a mechanism that does not involve alterations in BP.…”

Section: Alterations In Aldosterone Responsivenesssupporting

confidence: 72%

“…It is here that aldosterone governs the vectorial transport of water and electrolytes by acting as the principal ligand for the MR. Immunohistochemical labeling of isolated rat preglomerular vasculature [5] and glomeruli [4] for MR has also been documented. Studies by Ullian and coworkers have shown that aldosterone can directly stimulate citrate synthase in isolated glomeruli from Wistar rats [6]. Aldosterone has long been known to stimulate citrate synthase, a Krebs cycle enzyme, in the kidney and the heart [7] and by doing so may enhance mitochondrial oxidative phosphorylation and oxygen free radical generation.…”

Section: Introductionmentioning

confidence: 99%

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Effect of Aldosterone and MR Blockade on the Brain and the Kidney

2005

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The renin-angiotensin-aldosterone system (RAAS) plays a central role in the development of hypertension and the progression of end-organ damage. Although angiotensin-I converting enzyme (ACE) inhibitors and angiotensin II (Ang II) subtype-1 (AT(1)) receptor antagonists can initially suppress plasma aldosterone, it is now well established that aldosterone escape may occur whereby aldosterone levels return to, or exceed, baseline levels. The classical effects of aldosterone relate mainly to its action on epithelial cells to regulate water and electrolyte balance. However, the presence of mineralocorticoid receptors (MR) at nonepithelial sites in the brain, heart and vasculature, is consonant with the fact that aldosterone also has direct effects in these tissues. Substantial evidence now exists that supports the action of aldosterone at non-epithelial sites which in turn provokes a number of deleterious effects on the cardiovascular system including necrosis and fibrosis of the vasculature and the heart, vascular stiffening and injury, reduced fibrinolysis, endothelial dysfunction, catecholamine release and production of cardiac arrhythmias. Several studies have now shown that vascular and target-organ protective effects of MR antagonism occurs in the absence of significant blood pressure lowering or fluid loss, which is consistent with a major role for endogenous mineralocorticoids as direct mediators of cardiovascular injury. Adverse cardiovascular effects may occur in response to aldosterone alone, activation of the RAAS or aldosterone escape during chronic ACE inhibition or AT(1) receptor antagonism. The specific blockade of aldosterone action should prove to be of great therapeutic value in the prevention of cerebral and renal vascular disease and associated end-organ damage.

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Section: Alterations In Aldosterone Responsivenesssupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Effect of Aldosterone and MR Blockade on the Brain and the Kidney

2005

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“…Experimental models with reduced glomerular citrate synthase activity are protected from remnant nephropathy [36]. It can be hypothesized that changes in intracellular citrate concentration may also have direct actions.…”

Section: Citrate Effectsmentioning

confidence: 99%

Calcium citrate ameliorates the progression of chronic renal injury

Gadola

Noboa

Márquez

et al. 2004

Kidney International

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“…In the reduced renal mass model, animals develop remnant nephropathy characterized by augmented citrate synthase activity, plasma aldosterone levels and activity, and development of glomerular hypertrophy, adrenal hypertrophy, arterial hypertension, proteinuria, and structural renal injury in most animals. These effects, including plasma aldosterone levels, are decreased when the animals undergo subtotal nephrectomy with adrenalectomy [35][36][37][38][39]. Similarly, animal models that either lack aldosterone (adrenalectomized Sprague-Dawley rats) or are resistant to aldosterone actions (Wistar-Furth rats) are characterized by resistance to remnant nephropathy [36,[38][39][40][41].…”

Section: Aldosterone Synthesis and Receptorsmentioning

confidence: 99%

“…These effects, including plasma aldosterone levels, are decreased when the animals undergo subtotal nephrectomy with adrenalectomy [35][36][37][38][39]. Similarly, animal models that either lack aldosterone (adrenalectomized Sprague-Dawley rats) or are resistant to aldosterone actions (Wistar-Furth rats) are characterized by resistance to remnant nephropathy [36,[38][39][40][41]. If aldosterone is reinstituted via an infusion, it markedly increases the blood pressure in adrenalectomized spontaneously hypertensive rats [42], induces lesions of malignant nephrosclerosis in the deoxycorticosterone acetate-salt hypertensive rat model [43], and restores proteinuria and glomerulosclerosis in remnant rats treated with losartan and enalapril to an extent similar to that seen in untreated remnant rats [44].…”

Section: Aldosterone Synthesis and Receptorsmentioning

confidence: 99%

RAAS escape: A real clinical entity that may be important in the progression of cardiovascular and renal disease

Lakkis¹,

Lü²,

Weir

2003

Current Science Inc

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Interruption of the renin-angiotensin-aldosterone system (RAAS) at different levels is target-organ protective in several disease states; however, complete blockade is unlikely to be achieved due to escape mechanisms whenever blockade is attempted, incomplete knowledge of the role of all elements of the RAAS, and lack of pharmacotherapy against some elements that have been shown to contribute to disease states. Aldosterone has been overlooked as a mediator of RAAS escape and a key factor in target-organ injury despite the use of available RAAS blockers. Aldosterone is thought to play a role in the development of hypertension, alteration in vascular structure, vascular smooth muscle hypertrophy, endothelial dysfunction, structural renal injury, proteinuria, left ventricular remodeling, collagen synthesis, and myocardial fibrosis. Aldosterone receptor antagonists have been shown to antagonize all these effects in experimental models. Clinical trials with aldosterone antagonists showed an improvement in survival and left ventricular mass index in patients with congestive heart failure, and a reduction in urinary protein excretion and left ventricular mass index in patients with type 2 diabetes and early nephropathy who developed aldosterone synthesis escape. Consequently, aldosterone receptor antagonists may have specific benefits for reducing target-organ injury, particularly if there is evidence of RAAS escape.

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Potential importance of glomerular citrate synthase activity in remnant nephropathy

Abstract: Citrate synthase activity is elevated in remnant glomeruli, and experimental models characterized by reduced glomerular citrate synthase activity (Wistar-Furth rats, adrenalectomized Sprague-Dawley rats) are protected from remnant nephropathy.

Cited by 6 publications

References 20 publications

Effect of Aldosterone and MR Blockade on the Brain and the Kidney

Effect of Aldosterone and MR Blockade on the Brain and the Kidney

Calcium citrate ameliorates the progression of chronic renal injury

RAAS escape: A real clinical entity that may be important in the progression of cardiovascular and renal disease

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