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Biomedical subjects

R G Narins

Publications and source records attributed to R G Narins.

At least 19 recordsLinked to original sources
PubMed1996

Regulation of glomerular volume in normal and partially nephrectomized rats.

Glomerular extracellular matrix accumulation may derive from the stretching of mesangial cells caused by excessive glomerular dilatation. The relationship of glomerular volume (VG) to intraglomerular pressure, expressed as compliance or as mean VG in the isolated, perfused rat glomerulus, was used to analyze factors that regulate VG. Glomeruli were highly distensible over the normal and relevant abnormal range of pressure. Compliance increased directly with basal VG (P < 0.001), i.e., larger glomeruli dilated more than smaller ones at any given pressure. Perfusion with atrial natriuretic peptide did not alter compliance, and inhibitors of nitric oxide synthesis exerted only a trivial effect. VG expansion was consistently reduced by angiotensin II, but this effect was small (3.8%, P < 0.001). After subtotal nephrectomy, compliance increased by 59% in the remnant glomeruli (P < 0.001); 22% of this increase was attributable to structural changes, and the remainder was attributable to the large basal VG of the hypertrophied glomeruli. Thus the major determinants of VG expansion include capillary wall tension, basal VG, and intrinsic distensibility, which is markedly influenced by the character of the extracellular matrix and only slightly altered by an angiotensin II-modified mesangial cell tone.

Animals↗
PubMed1996

Cyclic stretching force selectively up-regulates transforming growth factor-beta isoforms in cultured rat mesangial cells.

Glomerular distention from increased intraglomerular pressure stretches mesangial cells (MCs). Stretching MCs in culture stimulates extracellular matrix accumulation, suggesting that this may be a mechanism for glomerular hypertension-associated glomerulosclerosis. We examined whether mechanical stretching serves as a stimulus for the synthesis and activation of the prosclerotic molecule transforming growth factor (TGF)-beta, thus providing a potential system for auto-induction of extracellular matrix. Rat MCs cultured on flexible-bottom plates were subjected to cyclic stretching for up to 3 days and then assayed for TGF-beta mRNA, secretion of TGF-beta, and localization of active TGF-beta by immunostaining. MCs contained mRNA for all three mammalian isoforms of TGF-beta. Cyclic stretching for 36 hours increased TGF-beta1 and TGF-beta3 mRNA levels approximately twofold, without altering the levels of TGF-beta2 mRNA. This was followed at 48 to 72 hours by the increased secretion of both latent and active TGF-beta1. Latent, but not active, TGF-beta3 secretion also increased whereas the levels of TGF-beta2 were unaffected by mechanical force. The stretching force in this system is unequally distributed over the culture membrane. Localization of active TGF-beta by immunostaining demonstrated that the quantity of cell-associated cytokine across the culture was directly proportional to the zonal amplitude of the stretching force. These results demonstrate that stretching force stimulates MCs to selectively release and activate TGF-beta1. This mechanical induction of TGF-beta1 may help explain the increased extracellular matrix associated with intraglomerular hypertension.

Animals↗
PubMed1992

Might distal renal tubular acidosis be a proximal tubular cell disorder?

Incomplete renal tubular acidosis (RTA) and overt distal RTA may be different stages of the same underlying pathophysiology in certain individuals. The rationale that draws these conditions together is the relatively alkaline pH of the urine, hypocitraturia, and a possible familial association. The rate of excretion of ammonium (NH4+), on the other hand, suggests that these conditions stem from fundamentally different lesions. To explain this difference, we suggest that two possible disorders may result in the evolution from incomplete RTA to overt distal RTA. One subgroup could have gradient-limited distal RTA, while the other subgroup may have a lower pH of the intracellular fluid of the proximal convoluted tubular epithelium. Indices of proximal intracellular pH (rates of excretion of NH4+, NH3, and citrate) were culled from the literature spanning the years 1959 to 1991 on patients with incomplete RTA and overt distal RTA. Three points emerge: (1) the rate of excretion of NH4+ was lower in patients with overt distal RTA than in normals following an acute acid load (23 +/- 1 v 49 +/- 3 mumol/min); (2) the concentration of NH3 in the urine was almost 25-fold higher in incomplete RTA than in normals (69 +/- 14 v 3 +/- 0.4 nmol/min); and (3) in incomplete RTA, the pH of the urine fell to very low values (4.9 +/- 0.1) when high urine flows were induced with furosemide. The low pH of the urine would therefore suggest that many of these patients do not gradient-limited distal RTA, but more likely have proximal renal epithelial cell acidosis. We hypothesize that this high rate of excretion of NH4+ and low rate of excretion of citrate in the absence of acidosis or hypokalemia is consistent with proximal cell acidosis. To explain a transition from incomplete RTA to overt distal RTA, we speculate that toxicity of high concentrations of NH3 in the medullary interstitium as well as nephrolithiasis and nephrocalcinosis due to low urinary citrate and possibly an alkaline medullary interstitium may lead to damage of structures in this region.

Acid-Base Equilibrium↗
PubMed1992

Intraglomerular pressure and mesangial stretching stimulate extracellular matrix formation in the rat.

To define the interplay of glomerular hypertension and hypertrophy with mesangial extracellular matrix (ECM) deposition, we examined the effects of glomerular capillary distention and mesangial cell stretching on ECM synthesis. The volume of microdissected rat glomeruli (Vg), perfused ex vivo at increasing flows, was quantified and related to the proximal intraglomerular pressure (PIP). Glomerular compliance, expressed as the slope of the positive linear relationship between PIP and Vg was 7.68 x 10(3) microns 3/mmHg. Total Vg increment (PIP 0-150 mmHg) was 1.162 x 10(6) microns 3 or 61% (n = 13). A 16% increase in Vg was obtained over the PIP range equivalent to the pathophysiological limits of mean transcapillary pressure difference. A similar effect of renal perfusion on Vg was also noted histologically in tissue from kidneys perfused/fixed in vivo. Cultured mesangial cells undergoing cyclic stretching increased their synthesis of protein, total collagen, and key components of ECM (collagen IV, collagen I, laminin, fibronectin). Synthetic rates were stimulated by cell growth and the degree of stretching. These results suggest that capillary expansion and stretching of mesangial cells by glomerular hypertension provokes increased ECM production which is accentuated by cell growth and glomerular hypertrophy. Mesangial expansion and glomerulosclerosis might result from this interplay of mechanical and metabolic forces.

Animals↗
PubMed1991

Diabetic nephropathy: can the natural history be modified?

Those diabetic patients who progress to advanced kidney disease constitute a subpopulation that is particularly vulnerable to the angiotoxic effects of the insulin-dependent disorder. Until the predisposing factors are identified, the most effective way to arrest renal deterioration is by controlling those currently recognized risk factors that accelerate the glomerulopathy. Treatments that normalize blood pressure, reduce dietary protein intake, and control hyperglycemia have been shown to retard the progression of diabetic nephropathy.

Animals↗
PubMed1991

Natriuretic effect of calcium-channel blockers in hypertensives.

This double-blind, randomized, crossover trial characterizes the acute natriuretic response to calcium-channel blockers (CCB) and investigates the role of hemodynamic and hormonal factors in mediating the natriuresis. Thirteen male subjects with essential hypertension received a single oral 20-mg dose of nifedipine or 120 mg of diltiazem. Renal functional and hemodynamic measurements were performed prior to and hourly for 4 hours following medication. Subjects then received these medications for 4 weeks at which time the above studies were repeated. Urinary sodium excretion increased within 60 minutes of CCB administration and the natriuresis was sustained for 4 hours. Cumulative sodium loss during the 4 hours of study was greater with nifedipine (43 +/- 12 mmol) than with diltiazem (18 +/- 6 mmol) (P less than 0.05). Despite natriuresis, urinary potassium excretion was decreased by both agents. Even though both drugs decreased the mean arterial pressure, inulin and paraaminohippurate (PAH) clearances were not altered. Plasma aldosterone concentrations decreased, plasma catecholamine concentrations increased, whereas plasma-renin activity was unchanged with both drugs. Body weight, glomerular filtration rate (GFR), renal plasma flow, plasma-renin activity, plasma aldosterone, and catecholamine concentrations were unchanged following 4 weeks of therapy. The acute natriuretic response after 4 weeks of therapy was similar to the response noted after the first dose. This study concludes that CCB are acutely natriuretic. Despite systemic hypotension, renal hemodynamics are unaltered during CCB therapy. Suppression of aldosterone as well as direct tubular effects of these drugs may mediate the natriuresis. Chronic therapy with CCB does not modify the acute natriuretic response to these agents.

Adult↗
PubMed1990

Hypokalemia and cardiovascular disease.

A growing body of experimental, epidemiologic and physiologic evidence testifies to the hazards of hypokalemia and other electrolyte disorders that can complicate the chronic use of diuretic drugs in patients with cardiovascular disease. This study reviews the complex renal and extrarenal mechanisms that regulate potassium balance in normal persons with special attention to the role of stress-related hormones. Disturbances of potassium balance are common in patients taking diuretics; indeed, the potential number of people in this country at risk of diuretic-related hypokalemia approaches 9 million. The magnitude of this problem is of particular concern, because of the compelling data that link hypokalemia in such patients to electrical instability of the heart and to a fatal outcome after an acute cardiac injury. Therefore, aggressive correction of hypokalemia is warranted in patients with cardiovascular disorders.

Cardiovascular Diseases↗
PubMed1989

Angiotensin converting enzyme inhibitors and progressive renal insufficiency. Current experience and future directions.

STUDY OBJECTIVE: To review the rationale for using angiotensin converting enzyme (ACE) inhibitors in progressive renal disease, and to evaluate the experience with these agents in patients with hypertension and renal insufficiency. DATA IDENTIFICATION: Experimental and clinical studies published from January 1977 to November 1988 were identified by searching the literature and by extensive hand searching of bibliographies of identified articles. STUDY SELECTION: Experimental studies of glomerular function during therapy with ACE inhibitors or other antihypertensive regimens were reviewed. Series using ACE inhibitors for treating hypertensive patients with renal disease were evaluated and reports of adverse events were studied. RESULTS OF DATA SYNTHESIS: Experimentally, ACE inhibitors seem to decrease glomerular injury by reducing both systemic and glomerular hypertension. Clinically, ACE inhibitors reduce systemic blood pressure in hypertensive patients with diabetic and nondiabetic renal disease without causing dramatic changes in glomerular filtration rate or renal blood flow. Most studies of nondiabetic renal insufficiency suggest that proteinuria is reduced in most patients. However, no long-term controlled study on the effect of ACE inhibitors on the progression rate of nondiabetic renal disease has been completed. ACE inhibitors have not yet been approved by the Food and Drug Administration (FDA) for treating or preventing progressive renal disease. Such use would therefore be considered "innovative" therapy. CONCLUSIONS: ACE inhibitors are tolerated by azotemic patients, although transient reductions in renal function can occur. Patients with bilateral renal insufficiency or low cardiac output are at increased risk for developing reversible acute renal insufficiency. Hyperkalemia may occur, particularly in patients with diabetes or severe renal insufficiency. In many patients with renal disease, ACE inhibitors dramatically reduce proteinuria, but whether they also reduce the rate of progression of renal disease remains unproved.

Angiotensin-Converting Enzyme Inhibitors↗