Salt restriction inhibits renal growth and stabilizes injury in rats with established renal disease.

Salt restriction inhibits renal growth and stabilizes injury in rats with established renal disease. Male Munich-Wistar rats that underwent right nephrectomy and segmental infarction of two thirds of the left kidney were fed standard chow for 4 wk and then randomly assigned to ingest standard or low-salt chow for an additional 4 wk. Four wk after ablation, rats had systemic hypertension, proteinuria, and glomerular sclerosis. The prevalence of sclerosis, protein excretion rate, and glomerular volume increased between the fourth and eighth week in rats that were fed standard chow, however, in rats that were fed low-salt chow, the increase in glomerular volume and development of further glomerular sclerosis was prevented whereas the protein excretion rate actually declined. Micropuncture studies performed 8 wk after ablation revealed that the glomerular hydraulic pressure was elevated in remnant kidneys and was not affected by salt restriction. This study demonstrates that dietary salt restriction can prevent further glomerular injury and reduce proteinuria even when instituted in rats with established renal disease. These findings are also consistent with the hypothesis that glomerular hypertrophy promotes injury in this model of hypertension and progressive renal disease.

Induction of myocardial insulin-like growth factor-I gene expression in left ventricular hypertrophy.

BACKGROUND: Left ventricular hypertrophy is a generalized adaptation to increased afterload, but the growth factors mediating this response have not been identified. To explore whether the hypertrophic response was associated with changes in local insulin-like growth factor-I (IGF-I) gene regulation, we examined the induction of the cardiac IGF-I gene in three models of systolic hypertension and resultant hypertrophy. METHODS AND RESULTS: The model systems were suprarenal aortic constriction, uninephrectomized spontaneously hypertensive rats (SHR), and uninephrectomized, deoxycorticosterone-treated, saline-fed rats (DOCA salt). Systolic blood pressure reached hypertensive levels at 3 to 4 weeks in all three systems. A differential increase in ventricular weight to body weight (hypertrophy) occurred at 3 weeks in the SHR and aortic constriction models and at 4 weeks in the DOCA salt model. Ventricular IGF-I mRNA was detected by solution hybridization/RNase protection assay. IGF-I mRNA levels increased in all three systems coincident with the onset of hypertension and the development of ventricular hypertrophy. Maximum induction was 10-fold over control at 5 weeks in the aortic constriction model, 8-fold at 3 weeks in the SHR, and 6-fold at 6 weeks in the DOCA salt model. IGF-I mRNA levels returned to control values by the end of the experimental period despite continued hypertension and hypertrophy in all three systems. In contrast, ventricular c-myc mRNA content increased twofold to threefold at 1 week and returned to control levels by 2 weeks. Ventricular IGF-I receptor mRNA levels were unchanged over the time course studied. The increased ventricular IGF-I mRNA content was reflected in an increased ventricular IGF-I protein content, as determined both by radioimmunoassay and immunofluorescence histochemistry. CONCLUSIONS: We conclude that (1) hypertension induces significant increases in cardiac IGF-I mRNA and protein that occur coordinately with its onset and early in the development of hypertrophy, (2) IGF-I mRNA levels normalize as the hypertrophic response is established, (3) in comparison to IGF-I, both c-myc and IGF-I receptor genes are differentially controlled in experimental hypertension. These findings suggest that IGF-I may participate in initiating ventricular hypertrophy in response to altered loading conditions. The consistency of these findings in models of high-, moderate-, and low-renin hypertension suggests that they occur independently of the systemic renin-angiotensin endocrine axis.

Calcium antagonists and converting enzyme inhibitors reduce renal injury by different mechanisms.

Both glomerular hypertension and hypertrophy have been associated with the development of glomerular injury in models of hypertension and reduced renal mass. The purpose of this study was to examine the effects of antihypertensive therapy on these parameters in the remnant kidney model of progressive glomerular sclerosis. Rats underwent 5/6 nephrectomy and were randomly assigned to receive either no therapy, the calcium entry blocker (CEB), nifedipine, or the angiotensin converting enzyme inhibitor (CEI), enalapril. Administration of either drug was associated with a reduction in systemic blood pressure and in the severity of glomerular injury assessed eight weeks after renal ablation. Micropuncture studies four weeks after ablation revealed that systemic and glomerular capillary pressure were high in untreated remnant kidney rats and reduced by enalapril. Administration of nifedipine was associated with a decline in systemic pressure, however, plasma renin levels increased, causing efferent arteriolar vasoconstriction and persistence of glomerular hypertension. Morphometric analysis showed that kidney weight, glomerular volume and glomerular capillary radius were lower in nifedipine treated rats than in the other two groups, indicating that the CEB, but not enalapril, inhibited the hypertrophic response to ablation of renal mass. Therefore, both CEIs and CEBs reduce glomerular injury in rats with remnant kidneys but they may act by different mechanisms. CEI reduce glomerular capillary pressure while CEBs inhibit compensatory kidney growth.

Effects of salt restriction on renal growth and glomerular injury in rats with remnant kidneys.

Male Munich-Wistar rats underwent right nephrectomy and infarction of two thirds of the left kidney. Rats were randomly assigned to ingest standard chow (REM) or a moderately salt restricted chow (LS). A third group of rats were fed the low salt diet and were injected with an androgen (LSA). Eight weeks after ablation, glomerular volume and glomerular capillary radius were markedly increased in REM. This increase was prevented by the low salt diet, however, the antihypertrophic effect of the diet was overcome by androgen. Values for glomerular volume and capillary radius were similar in LSA and REM. Morphologic studies revealed that approximately 25% of glomeruli were abnormal in REM. Much less injury was observed in salt restricted rats, however, the protective effect of the low salt diet was significantly abrogated when renal growth was stimulated in salt restricted rats by androgen. Micropuncture studies revealed that glomerular pressure was elevated in all three groups and not affected by diet or androgen. Serum cholesterol was also similar in the three groups. These findings indicate that renal and glomerular hypertrophy are correlated with the development of glomerular injury after reduction in renal mass and suggest that dietary salt restriction lessens renal damage, at least in part, by inhibiting compensatory renal growth.

Renal vascular effects of calcium channel blockers in hypertension.

Recent evidence suggests that calcium channel blockers have specific effects on renal hemodynamics in patients with hypertension and may also slow the progression of chronic renal failure. When these agents are studied in vitro, their predominant effect is to reverse afferent arteriolar vasoconstriction induced by catecholamines or angiotensin II. Because efferent resistance may remain high, glomerular filtration rate rises while renal blood flow remains low. The effects in vivo are less consistent. In human hypertension, calcium channel blockers lower renal resistance and may raise both renal blood flow and glomerular filtration rate. In experimental models of chronic renal disease, calcium channel blockers slow the progression of renal damage; however, variable effects on renal hemodynamics have been found. Other factors implicated in the progression of renal damage, including compensatory renal hypertrophy, platelet aggregation, and calcium deposition, may also be favorably influenced by these agents. Recent studies suggest that calcium channel blockers may have similar protective effects in patients with hypertension and chronic renal disease.

Effects of nifedipine and enalapril on glomerular injury in rats with deoxycorticosterone-salt hypertension.

Male Munich-Wistar rats underwent right nephrectomy and were given weekly injections of deoxycorticosterone acetate (DOCA) and 1% saline (salt) to drink. Two studies were performed. In the first, rats given enalapril (ENP) were compared with controls. In the second, rats ingested either standard chow or chow to which the calcium-entry blocker nifedipine (NIF) had been added. Six to eight weeks after nephrectomy, both control DOCA-salt rats and those given ENP had severe hypertension and significant proteinuria. Rats given NIF excreted less protein, and glomerular lesions were not observed in this group. The effects of NIF on several parameters that have been associated with glomerular injury were examined. Micropuncture studies revealed that glomerular capillary pressure was increased in DOCA-salt rats and was not reduced by NIF. Platelet aggregation was also similar in NIF-treated and control rats. Morphometric studies revealed a tendency toward lower glomerular volume of NIF-treated rats; however, kidney weight and glomerular capillary radius were unaffected by therapy. Thus NIF, but not ENP, prevents DOCA-salt rats from developing hypertension and glomerular injury. This effect does not depend on reduction in glomerular pressure or inhibition of platelet aggregation.

Superiority of salt restriction over diuretics in reducing renal hypertrophy and injury in uninephrectomized SHR.

Spontaneously hypertensive rats (SHR) were uninephrectomized (UNX) at 6 wk of age and given either standard chow (CON), low-sodium chow (LSC), or standard chow and hydrochlorothiazide (HCTZ) added to the drinking water. Severe hypertension developed in all three groups. Forty-two weeks after UNX, proteinuria and glomerular sclerosis were significantly lower in LSC than in CON or HCTZ. The protective effect of salt restriction did not depend upon alterations in plasma renin concentration or glomerular hemodynamics. Micropuncture revealed that glomerular pressure was high in all three groups. Renal hypertrophy assessed by kidney weight, kidney-to-body weight ratio, glomerular volume, and glomerular capillary radius were reduced by salt restriction. These findings suggest that, in the setting of glomerular hypertension, hypertrophy promotes sclerosis. Salt restriction inhibits compensatory kidney growth and protects the kidney.

Impact of antihypertensive therapy on progressive kidney damage.

Our ability to measure precisely the pressures and flows within the glomerular microcirculation has enabled us to begin to unravel the complex relationship between systemic hypertension and kidney disease. Although a number of factors have been implicated in the development of glomerular sclerosis, one consistent finding has been that glomerular injury occurs when elevated pressures are transmitted to the glomerular capillaries. Intrarenal hypertension, in conjunction with renal hypertrophy, and, possibly, disturbances in lipid metabolism and blood coagulation constitute secondary processes through which those nephrons not severely injured by the primary renal disease are eventually destroyed. Ultimately, all renal function is lost. Clinically, increased glomerular pressure is likely to contribute to glomerular injury in those patients in whom hypertension and renal insufficiency coexist. In patients with diabetes, as yet unidentified factors cause preglomerular resistance to fall so that glomerular hypertension develops even in the absence of elevation in systemic blood pressure. Although no therapy has been proven to slow the rate of progression to end stage renal failure in humans, a number of promising interventions have been identified. These include dietary protein or salt restriction, and medication, with either converting enzyme inhibitors or calcium channel blockers.