Role of Citrate Synthase in Aldosterone-Mediated Sodium Reabsorption

Abstract

Abstract-Aldosterone and other mineralocorticoids increase citrate synthase activity in the kidney and enhance renal sodium reabsorption, but it is unclear whether the increased citrate synthase activity is involved in renal sodium transport. We used the Wistar-Furth rat, an inbred strain found to be deficient in renal citrate synthase activity, as an experimental model to investigate this issue. We confirmed that renal citrate synthase activity from adrenalectomized Wistar-Furth rats was decreased compared with that from control Wistar rats (by 28% T he mineralocorticoid aldosterone stimulates activity of certain key enzymes in the tricarboxylic acid cycle (eg, citrate synthase) in the rat kidney. 1-5 Adrenalectomy reduces renal citrate synthase activity, and the administration of aldosterone to adrenalectomized animals restores citrate synthase activity. 4 These findings arose from an ongoing effort to identify aldosterone-induced proteins (ie, proteins synthesized in response to the transcription factor activity of the occupied mineralocorticoid receptor) and to determine how these proteins mediate the classic action of mineralocorticoids: renal sodium reabsorption. It has been hypothesized that enhancement of citrate synthase activity increases ATP formation and, subsequently, activity of Na ϩ ,K ϩ -ATPase and sodium reabsorption in the distal nephron. This schema is consistent with the "energy hypothesis" of aldosterone action.However, the correlation of aldosterone-induced enhancement of renal citrate synthase activity with aldosteroneinduced stimulation of sodium reabsorption has been investigated in only a few studies, and the results have been inconsistent. At 3 to 4 hours after aldosterone was injected into rats, both a maximum increase in renal citrate synthase activity and a maximum decrease in urinary sodium-topotassium ratio were observed. 3 Other studies have been performed in cultured cell lines. In toad bladder and toad kidney cells, aldosterone stimulated sodium transport without an increase in citrate synthase activity. 6 In another study, aldosterone stimulated both vectorial sodium transport and citrate synthase activity in toad bladder cells, whereas aldosterone stimulated sodium transport in the absence of an increase in citrate synthase activity in A6 cells. 7 In the present study, we used Wistar-Furth rats (WF) as an experimental model to investigate the role of citrate synthase activity in aldosterone-mediated sodium reabsorption. WF, which were bred from normal Wistar rats (W), have been shown to be resistant to the development of mineralocorticoid-excess hypertension. 8 -13 During the biochemical evaluation of the mechanisms that underlie this resistance to mineralocorticoids, we observed that basal and aldosterone-stimulated citrate synthase activities in whole kidney were markedly reduced in WF compared with W. 13

Involvement of Tricarboxylic Acid Cycle Metabolites in Kidney Diseases

“…In non-diabetic CKD patients, the expressions of aconitase 1 and aconitase 2 are reduced; and in urine and blood, the levels of isocitrate are also decreased [ 42 ]. In addition, it is known that CS is stimulated by aldosterone [ 48 ], a hormone increased in CKD [ 49 ], suggesting that in CKD, aldosterone promotes an excess of citrate synthesis. This suggests that produced citrate (probably in excess) is not converted into isocitrate, and its retention results in the reduced urinary excretion [ 42 ], as has been demonstrated in animal models of UUO-induced CKD and I/R-induced AKI, in which kidney tissue reveals an accumulation of this metabolite [ 46 , 50 ].…”

Potential importance of glomerular citrate synthase activity in remnant nephropathy

“…5), regardless function. The mineralocorticoid receptor, the initial aspect of the aldosterone signal transduction pathway, has been WF [17] and because aldosterone stimulates hypokashown to be abnormal in humans with aldosterone resislemia equally well in W and WF [1,10]. Nothing is known tance, that is, pseudohypoaldosteronism [19,20].…”

“…The fact that renal tubular responses of WF to aldosterone. Glomeruli were exposed to 100 nmol/L analdosterone in vivo appeared to be normal [17] also digiotensin II for 30 minutes or two hours ex vivo, and rected our studies away from the tubulointerstitium and then CS activity was measured. Angiotensin II did not toward the glomerulus.…”

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

“…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].…”

“…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].…”