Abnormal regulation of proximal tubule renin mRNA in the Dahl/Rapp salt-sensitive rat.

BACKGROUND: The precise pathogenesis of salt-sensitive hypertension in the Dahl rat is unknown. Abnormalities in renal hemodynamics and NaCl handling have been implicated, and may relate to changes in the activity of the intrarenal renin-angiotensin system. METHODS: Circulating, juxtaglomerular and intrarenal (glomerular and proximal tubular) renin were studied in Dahl/Rapp salt-sensitive and salt-resistant rats fed with a normal (0.5%) or high (4%) NaCl diet. Circulating and juxtaglomerular renin were assessed by measurement of plasma renin activity and renin secretory rates. Glomerular and proximal tubular renin mRNA were assessed by microdissection and quantitative competitive RT-PCR. RESULTS: Circulating and juxtaglomerular renin were suppressed by high dietary NaCl in salt-sensitive rats (plasma renin activity, 0.5%, 10.9 +/- 0.7 vs. 4%, 7.9 +/- 0.3 ng/ml/hr, P < 0.05; renin secretory rate, 0.5% 220 +/- 32 vs. 4%, 58 +/- 5 ng/mg/hr, P < 0.05). Glomerular renin mRNA was also suppressed by the higher salt diet in salt-sensitive animals (0.5%, 411 +/- 84 vs. 4%, 67 +/- 22 x 103 copies/glomerulus, P < 0.05). In contrast, proximal tubular renin was not suppressed by a high NaCl diet in salt-sensitive animals (0.5%, 13.9 +/- 2.7 vs. 4%, 12.1 +/- 3.6 x 103 copies/mm tubule, P = NS), but was suppressed in salt-resistant rats (0.5%, 9.5 +/- 2.8 vs. 4%, 3.2 +/- 1.2 x 103 copies/mm, P < 0. 05). CONCLUSIONS: Failure to suppress proximal tubular renin in response to high dietary NaCl may result in increased local generation of angiotensin II and enhanced proximal tubular NaCl absorption, and thereby contribute to the generation of salt sensitive hypertension.

Regulation of glomerular and proximal tubule renin mRNA by chronic changes in dietary NaCl.

Renal adaptations to chronic changes in dietary NaCl and extracellular fluid volume involve both glomerular and tubular mechanisms that result in preservation of glomerular filtration rate and modifications of renal tubular transport to secure external NaCl balance. Although the systemic renin-angiotensin system (RAS) mediates some of these responses, the possible contributions of local glomerular and proximal tubule RASs in these adaptations have not been examined. Thus, in this study, glomeruli and proximal tubules were microdissected from rats adapted to high (4.0%), normal (0.5%), or low (0.01%)-NaCl diets, and renin mRNA was measured using quantitative competitive reverse transcription-polymerase chain reaction. After 4 days of the diets, glomerular renin mRNA abundance was increased 100% by the low-NaCl diet (P < 0.05) and suppressed 50% (P < 0.01) by the high NaCl diet compared with controls. Renin mRNA in proximal tubules was stimulated 230% (P < 0.05) by the low-NaCl diet and tended to be suppressed (68% decrease, not significant) by the high-NaCl diet. When the high-NaCl diet was continued for 2 wk, proximal tubule renin mRNA was suppressed by 89% (P < 0.05). This study provides evidence that glomerular and proximal tubule renin transcript levels are regulated by chronic changes in dietary NaCl, suggesting that local RASs contribute to the renal adaptations in response to chronic alterations in NaCl.

Differential regulation of rat glomerular and proximal tubular renin mRNA following uninephrectomy.

Angiotensin II is thought to play a role in the renal adaptations to reduced renal mass, but earlier work has shown that plasma renin activity (PRA) does not increase in this setting. To examine this paradox, we studied the effect of uninephrectomy (UNX) on circulating, juxtaglomerular, glomerular, and proximal tubular (PT) renin. PRA was unchanged 2 wk following UNX and fell slightly at 6 wk. Single kidney renin secretory capacity and cortical renin mRNA, reflecting juxtaglomerular renin, were unchanged at 2 and 6 wk. With quantitative competitive reverse transcription-polymerase chain reaction, renin mRNA in microdissected glomeruli and PT were dramatically increased 2 wk post-UNIX (for glomeruli: sham, 1.2 +/- 0.3, vs. UNX, 8.8 +/- 1.9 x 10(5) copies/glomerulus; for PT: sham, 4.6 +/- 0.9, vs. UNX, 17.7 +/- 5.1 x 10(3) copies/mm). By 6 wk, glomerular renin was unchanged, and PT renin mRNA was markedly suppressed (for glomeruli; sham, 2.9 +/- 1.2, vs. UNX, 4.2 +/- 1.1 x 10(5) copies/glomerulus; for PT: sham, 7.5 +/- 2.1, vs. UNX, 1.0 +/- 0.3 x 10(3) copies/mm). These results demonstrate differential regulation of the circulating, juxtaglomerular, glomerular, and PT renin systems. Early activation of glomerular and PT renin may result in increased local generation of angiotensin II and thereby affect renal structural and functional adaptations following UNX.

Altered renal vascular responses in the aging rat kidney.

Age-related renal functional changes may relate to alterations in the responsiveness to vasoconstrictors and vasodilators. Blood pressure and renal responses to angiotensin II (ANG II), endothelin-1 (ET), NG-nitro-L-arginine methyl ester (L-NAME), and to the ANG II receptor antagonist losartan were compared in young (3-mo-old) and older (15-mo-old) male rats. Baseline mean arterial pressure (MAP) values were slightly lower in the older rats, and glomerular filtration rate (GFR) and renal plasma flow (RPF) were higher. ANG II and ET induced comparable pressor responses in both groups but produced greater GFR and RPF reductions in the older rats. In contrast, the MAP, GFR, and RPF responses to L-NAME were exaggerated in aging rats. Losartan induced modest MAP reductions in both groups, and comparable renal vasodilatory responses. Thus the aging kidney exhibits exaggerated responses to systemic vasoconstrictor stimuli, whereas responsiveness to ANG II blockade is preserved but not enhanced. Whether or not this balance is further impaired later in the aging process remains to be determined.

Simultaneous "in series" hemodialysis and hemoperfusion in the management of valproic acid overdose.

There is little published experience with the extracorporeal treatment of valproic acid overdose, although the pharmacokinetic properties of valproic acid suggest a potential role for hemodialysis and/or hemoperfusion. At therapeutic concentrations valproic acid is highly protein bound, but at the higher concentrations seen in the overdose setting binding sites become saturated and free valproic acid should be subject to removal by hemodialysis. We report the case of a patient with serious toxicity secondary to valproic acid overdose who was successfully treated with a combination of hemodialysis and hemoperfusion. With this treatment the half-life of valproic acid was reduced from a predialysis level of 13 hours to 1.7 hours, with rapid lowering of valproic acid levels and dramatic clinical improvement. Based on our experience in this patient and a review of previously reported cases, hemodialysis should be considered in the treatment of valproic acid overdose.