Glomerular Hemodynamic Alterations Research Articles

The Zucker rat model of obesity, insulin resistance, hyperlipidemia, and renal injury.

Although the pathogenesis of obesity in OZR is unknown, the association among hyperinsulinemia, insulin resistance, and hyperlipidemia suggests that investigations using OZR may help define how a number of vascular disease risk factors interact to cause end-organ damage. Like other rat strains, OZR do not develop atherosclerosis spontaneously. Nevertheless, in an endothelial injury model, atherosclerosis was worse in OZR than in LZR. Perhaps more intriguing is the fact that OZR develop spontaneous glomerular injury. Although the mechanisms important in the development and progression of glomerular injury in OZR remain to be clarified, both lipid abnormalities and glomerular hemodynamic alterations could play a role.

Paleonephrology and Reflux Nephropathy

Urinary tract infections, in association with ureteral reflux or dysperistalsis, may lead to invasive renal parenchymal infection and residual scarring (reflux nephropathy). Such infections in infants are often not diagnosed during the acute phase. Late sequelae of reflux nephropathy include hypertension, proteinuria, or chronic renal failure. The latter may eventuate in the subset of patients with urinary tract infection and unilateral reflux extending to a solitary kidney or bilateral reflux. Proteinuria may herald the inexorable progression of glomerular sclerosis in patients destined to progress to end-stage renal disease, despite the absence of further recurrences of urinary tract infections. The mechanism of progression is probably similar to that occurring in other forms of chronic, diffuse parenchymal renal disease, which all have similar alterations in glomerular hemodynamics (an increase in glomerular capillary flow, pressure, and filtration). The consequent hyperfiltration per nephron may be related to the level of dietary protein intake or to some derivative of the protein load. Hyperfiltration appears to recapitulate the presumed renal hemodynamic response to the relatively high level of episodic meat consumption by paleolithic hunter-gatherers. A prudent therapeutic intervention in children with progressive reflux nephropathy may be a proportional reduction in protein intake.

Increased renal endothelin production in rats with reduced renal mass

Renal endothelin (ET) production was investigated in rats after renal mass ablation, a model of progressive renal disease characterized by glomerular hemodynamic alterations and capillary thrombosis, and in sham-operated animals. Thrombin stimulation of renal cortical tissue from rats with renal mass reduction, 45 but not 7 days after surgery, generated significantly (P less than 0.01) more ET than tissue from sham-operated animals. Exposure to thrombin of isolated glomeruli from remnant but not sham kidneys also significantly (P less than 0.01) increased ET production compared with unstimulated glomeruli. At day 45, in rats with renal mass ablation ET plasma levels were numerically lower, whereas urinary excretion rate of ET was significantly (P less than 0.01) increased compared with sham-operated animals. After a 50-min intravenous infusion of 125I-ET to normal rats and animals with renal mass ablation, less than 0.3% and 0.03%, respectively, of total infused radioactivity was recovered in urine. These results indicate that thrombin-stimulated ET production by renal cortical tissues is increased in rats with renal mass reduction. Despite normal or low-normal plasma ET levels, urinary excretion of the peptide is markedly increased in this model. The exogenously labeled ET added to circulation is not excreted by the kidney, suggesting that enhanced urinary excretion rate would reflect an increased renal production of the peptide in rats with remnant kidney.

Do glomerular hemodynamic adaptations influence the progression of human renal disease?

Although experiments in the rat suggest that glomerular hemodynamic alterations following a reduction of renal mass may be implicated in the progression of chronic renal failure, we argue that the deleterious effects of similar adaptations in human renal disease are unproven. In the otherwise normal solitary kidney the supranormal glomerular filtration rate (GFR) remains stable over the longterm, and in early diabetic nephropathy which is also accompanied by hyperfiltration, renal deterioration cannot be dissociated from a rise in systemic blood pressure. In patients with miscellaneous renal diseases and a depressed basal GFR there is indirect evidence that hyperfiltration might occur in some of the remnant glomeruli. However, at present there is little conclusive evidence to indicate that therapies which might normalize glomerular hemodynamics, e.g., dietary protein restriction, have any effect on progression of renal disease, or that angiotensin converting-enzyme inhibitors, which lower glomerular capillary pressure, have any advantage over other antihypertensive agents which are equally efficacious in lowering systemic blood pressure.

Induction of renal growth and injury in the intact rat kidney by dietary deficiency of antioxidants.

We report induction of renal growth and injury in the intact rat kidney using a diet deficient in vitamin E and selenium. This diet was imposed in 3-wk-old male weanling rats, and after 9 wk, enhancement of growth, characterized by increased wet weight, dry weight, protein content, and DNA content appeared. Morphometric analyses revealed increased kidney volume, tubular epithelial volume, and mean glomerular volume. There were no differences in nephron number. The animals on the deficient diet displayed increased urinary protein excretion at 9 wk. Renal injury was also characterized by an interstitial cellular infiltrate and diminutions in glomerular filtration rate. Enhanced growth and injury were antedated by increased renal ammoniagenesis. The deficient diet did not induce metabolic acidosis, potassium depletion, glucose intolerance, or elevated plasma amino acid concentration. Enhancement of renal growth and ammoniagenesis by the deficient diet was not suppressible by chronic alkali therapy. Stimulation of renal growth could not be ascribed to increased intrarenal iron, induction of ornithine decarboxylase, or alterations in glomerular hemodynamics. Stimulation of renal ammoniagenesis by dietary deficiency of antioxidants is a novel finding, as is induction of growth and injury. We suggest that increased renal ammoniagenesis contributes to induction of renal growth and injury.

Mechanism of the Unique Susceptibility of Deep Cortical Glomeruli of Maturing Kidneys to Severe Focal Glomerular Sclerosis

The alterations in single glomerular hemodynamics, glomerular size, and development of glomerular sclerosis after subtotal nephrectomy were assessed in approximately 32-d-old young and greater than 3-mo-old adult Munich-Wistar rats. In 6 wk, young rats developed more pronounced glomerular sclerosis and more marked elevation in blood urea nitrogen. The deep (versus superficial) cortical region of young rats was characterized by having a greater number of glomeruli with advanced sclerosis. Single nephron glomerular filtration rate of superficial glomeruli of the young increased to a much greater extent than whole kidney glomerular filtration rate, whereas there were comparable post-subtotal nephrectomy increases in whole kidney glomerular filtration rate in these two age groups, indicating that the deep glomeruli were exposed to a lesser hemodynamic load than were the superficial. Since the remnant nephrons of young and adult rats achieved equally high glomerular pressures and comparably large glomerular size shortly after subtotal nephrectomy, the unique susceptibility of young glomeruli to sclerosis is attributed to the intrinsic property of these glomeruli, rather than the abnormal hemodynamics or stimuli promoting hypertrophy and mesangial matrix accumulation imposed upon the glomeruli.

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.

Acute and subacute prostaglandin and ANG II inhibition on glomerulotubular dynamics in rats

Prostaglandins (PG) and angiotensin II (ANG II) contribute to regulation of glomerular microcirculation. Acute vs. chronic physiological alterations of glomerular hemodynamics that result from inhibition of either PG or ANG II, or both, and their interaction were examined. Four groups of Munich-Wistar rats were submitted to the following micropuncture studies in euvolemic conditions for measurements of glomerular hemodynamics and tubular fluid reabsorption: 1) an untreated control group, 2) 4- to 6-day inhibition of both PG and angiotensin-converting enzyme activity with meclofenamate and MK-421 (enalapril), 3) 4- to 6-day treatment with enalapril followed by acute PG inhibition in the second measurement period, 4) 4- to 6-day PG inhibition followed by acute enalapril treatment in the second period. Dual 4- to 6-day treatment decreased single-nephron filtration rate (SNGFR, 24 +/- 2 vs. 33 +/- 2 nl/min in control; P less than 0.05) as a result of decreases in single-nephron plasma flow (SNPF) and glomerular hydrostatic pressure gradient (delta P). Treatment with enalapril alone for 4-6 days did not reduce SNGFR and SNPF; however, delta P decreased. Acute addition of meclofenamate did not alter these factors. SNGFR was decreased with 4- to 6-day treatment of meclofenamate from 33 +/- 2 in control to 25 +/- 1 nl/min (P less than 0.05). Acute treatment with enalapril in the 4- to 6-day meclofenamate-treated rats increased SNGFR to values not different from control. The results demonstrated that glomerular hemodynamic alterations consequent to inhibition of ANG II and PG systems differ between chronic and acute treatments. Therefore, interpretation of the role of individual hormonal systems in the control of glomerular hemodynamics should be approached with caution, since effects may be altered by duration of treatment and involvement of other vasoactive systems.

Regulation of renal transport processes and hemodynamics by macrophages and lymphocytes

Inflammatory diseases of the renal glomerulus and interstitium are characterized by numerous alterations in renal glomerular hemodynamics and tubule transport processes. The cellular mechanisms underlying these changes have been theoretically attributed to nephron toxicity and destruction. However, recent studies suggest that many of the alterations in renal physiology may be mediated by specific immune cell-derived factors. Macrophages release a variety of cytokines on activation. One of these monokines, interleukin 1, induces a natriuresis by direct inhibition of collecting duct sodium reabsorption. Glomerular macrophages release highly vasoconstrictive compounds, including leukotriene D4 and thromboxane A2. Macrophages have now been demonstrated to migrate into the renal interstitium in diseases not previously considered to have an immunological component. Acute ureteral obstruction is characterized by a rapid infiltration of macrophages and lymphocytes into the kidney. Removal of the immune cell infiltrate in ureteral obstruction by irradiation markedly improves glomerular filtration rate and renal blood flow and partially corrects sodium and water excretion. Such immune modulation of renal function is likely to occur in a wide variety of diseases of the kidney, many of which do not involve a primary immunological insult. We propose that the abnormalities in renal hemodynamics and in the transport of fluid and electrolytes observed in states characterized by coexistence of immune cells among renal parenchymal cells may reflect a complex immune modulation of renal cell physiology.

Glomerular hemodynamic alterations during renal nerve stimulation in rats on high- and low-salt diets

Renal adrenergic nerve activity exerts a major influence on glomerular hemodynamics and tubular fluid reabsorption. Modulation of the functional expression of adrenergic activity in the kidney can be mediated, in part, by the renin-angiotensin system and by prostanoid activity. Alterations in dietary salt intake have been previously shown to modify the activity of various vasoactive systems, including angiotensin and prostaglandin activity and thereby have a potential of modifying the glomerular hemodynamic response to a given renal adrenergic stimulus. Munich-Wistar rats were fed either a high-, low-, or normal salt diet for 2 wk before the day of the study. Measurements of glomerular hemodynamics were performed in both unstimulated with basal renal nerve traffic eliminated and during exogenous renal nerve stimulation (RNS) (3 Hz). RNS decreased glomerular capillary hydrostatic pressure and single-nephron plasma flow to a similar extent in all three dietary conditions via increases in afferent arteriolar resistance. The data demonstrated that dietary preconditioning does not alter the glomerular hemodynamic response to an exogenous, fixed RNS. Glomerular prostaglandin E2 production and plasma renin activity were significantly greater in rats fed a low-salt diet compared with either normal- or high-salt diet. The constancy of glomerular hemodynamic responses to RNS in spite of wide variations in dietary salt intake indicates that functional renal hemodynamic differences observed as a result of NaCl intake must be primarily the consequence of differences in renal nerve traffic and not hormonal alterations.

Effects of beta 1-adrenergic blockade on glomerular dynamics and angiotensin II response

Adrenergic activity regulates renal function by several mechanisms. Renal nerves not only exert vasoconstrictor functions but also may influence glomerular hemodynamics by beta-adrenergic activity, especially via the effects on renin angiotensin activity. Little is known of the specific glomerular hemodynamic alterations resulting from beta 1-adrenergic blockade. Current studies examined the effects of 4-6 days of treatment with atenolol (50 mg/kg), a beta 1-selective adrenergic antagonist, on glomerular hemodynamics in plasma volume-expanded Munich-Wistar rats. Atenolol treatment reduced blood pressure both in the awake state and during micropuncture. This reduction in blood pressure contributed to a decrease in nephron filtration rate (48 +/- 1 in untreated rats vs. 40 +/- 1 nl.min-1.g kidney wt-1 in the atenolol-treated group, P less than 0.05) by reduction in nephron plasma flow (182 +/- 2 vs. 154 +/- 4 nl.min-1.g kidney wt-1 in the atenolol-treated rats). No other determinant of glomerular ultrafiltration was influenced by atenolol treatment. Since beta 1-adrenergic blockade may influence the generation of angiotensin II, the response to angiotensin II infusion was assessed and found not to differ from control untreated animals. These studies demonstrate that beta 1-receptor blockade reduced nephron filtration rate by decreasing mean arterial blood pressure and nephron plasma flow without significant modifications in vascular resistance and the glomerular hydrostatic pressure gradient.

Hypertension and Renal Diseases

Experimental data are summarized that provide evidence that enhanced transmission of systemic hypertension to the glomerulus occurs in the setting of reduced renal mass. It is proposed that similar adaptive glomerular hemodynamic alterations occur in parenchymal renal disease in humans, favoring the development of intraorgan hypertension. Accelerated vascular and glomerular damage and functional deterioration result. Treatment of systemic hypertension with agents that reduce glomerular capillary pressure has been shown to ameliorate the manifestations of experimental glomerular disease. The importance of preventing hemodynamic injury to the arterioles and glomerular capillaries in the management of human renal disease is stressed.

Regulatory role of prostanoids in glomerular microcirculation of remnant nephrons.

The glomerular microcirculation of the remnant nephron is characterized by reduced afferent (RA) and efferent (RE) arteriolar resistances and markedly increased single nephron glomerular plasma flow and filtration rates. We investigated the role of prostanoid production in mediating these adaptive alterations in glomerular hemodynamics after the reduction of renal mass. Acute administration of indomethacin, 5 mg/kg iv in anesthetized euvolemic, Sprague-Dawley rats with intact kidneys led to no significant alteration in renal hemodynamics, whereas in similarly prepared subtotally nephrectomized rats such inhibition significantly reduced remnant kidney glomerular filtration rate from 0.57 +/- 0.07 to 0.45 +/- 0.05 ml/min and single nephron glomerular filtration rate (SNGFR) from 93 +/- 4 to 72 +/- 5 nl/min. This reduction in SNGFR was due to diminutions in the glomerular ultrafiltration coefficient (Kf) from basal values of 0.061 +/- 0.004 to 0.050 +/- 0.004 nl X s-1 X mmHg-1 and in initial glomerular capillary plasma flow rate (QA) from 416 +/- 42 to 321 +/- 42 nl/min. The decrease in QA was a consequence of proportional increases in RA and RE. In other groups of animals we demonstrated that urinary excretions of both vasodilatory as well as vasoconstrictor prostanoids per surviving nephron increase several fold in subtotally nephrectomized rats compared with rats with intact kidneys and that administration of indomethacin, 5 mg/kg iv, reduced urinary excretions of both vasodilatory prostaglandins, prostaglandin E and 6-keto-prostaglandin F1 alpha, as well as vasoconstrictor prostanoid, thromboxane B2, to the same degrees in both subtotally nephrectomized rats and rats with intact kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)

High energy phosphates, phospholipids, and calcium in ischemic renal tubular cell injury.

Substantial data is available supporting critical roles for high energy phosphates, calcium, and phospholipids in ischemic cell injury. Although it has been proposed that one of these compounds may be most critical and defines the "final common pathway" for lethal cell injury, it is more accurate to define the pathogenesis of ischemic cell injury as the simultaneous derangement of several critical metabolic process which act in concert to produce a cascade of events that finally lead to plasma and subcellular membrane dysfunction incompatible with the maintenance of cell viability and integrity. As detailed in Figure 1, a tentative scheme is proposed interrelating high energy phosphate depletion, cellular calcium derangements, and membrane phospholipid degradation and loss. Ischemia directly leads to declines in the rate of oxidative phosphorylation due to a lack of oxygen availability. A fall in cellular ATP levels develops. Ischemia also promotes a redistribution of intracellular calcium pools and results in phospholipase activation and phospholipid degradation. When phospholipid degradation occurs concomitantly with a decline in high energy phosphate levels, phospholipid synthesis cannot keep pace with phospholipid degradation and net membrane phospholipid loss occurs. An increase in plasma membrane calcium permeability develops and the influx of calcium down its electrochemical gradient from extracellular to intracellular spaces occurs. This calcium is taken up and sequestered in mitochondria and causes further alterations in mitochondrial structure and function, leading to further declines in cellular ATP content.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of hypertension in renal disease.

Experimental and clinical evidence are summarized that support the hypothesis that enhanced transmission of systemic hypertension to the adapted glomerulus in the setting of reduced nephron mass may be responsible for accelerated vascular and glomerular damage in the hypertensive stage of parenchymal renal disease in man. In experimental models of hypertension associated with reduced renal mass, the kidney appears to be damaged directly by transmission of pressure rather than primarily through vasoconstriction and ischemia. When hypertension is combined with models of glomerular disease, vascular and glomerular injury are aggravated. It is proposed that adaptive glomerular hemodynamic alterations which occur in parenchymal renal disease magnify the transmission of increased pressure and flows when hypertension supervenes. Accelerated vascular and glomerular damage and functional deterioration result. According to this hypothesis, control of systemic hypertension and minimization of hydraulic stress on the diseased glomerulus become critical to the management of chronic renal disease and the prevention of progressive renal insufficiency.

Diabetic nephropathy. A perspective.

The earliest manifestations of clinical diabetic nephropathy, including proteinuria, hypertension, and declining GFR, represent very advanced diabetic glomerulopathy with especially prominent mesangial expansion. Mesangial expansion, by restricting glomerular capillary filtration surface and lumenal volume, stimulates compensatory mechanisms analogous to those resulting from a marked reduction in nephron number. These compensatory mechanisms involve alterations in glomerular hemodynamics designed to maintain glomerular filtration but which ultimately injure the kidney. These hemodynamic perturbations are not specific to diabetes but represent a final common pathway toward endstage renal failure that also characterizes the remnant kidney. This thesis concludes that the onset of clinical diabetic nephropathy augurs inevitable decline in kidney function, and that only studies and interventions exercised before clinical nephropathy develops can influence understanding and outcome of diabetic nephropathy.

Insulin requirement for contraction of cultured rat glomerular mesangial cells in response to angiotensin II: possible role for insulin in modulating glomerular hemodynamics.

One proposed role of glomerular mesangial cells is the regulation of glomerular blood flow by contraction. Alterations in the contractile activity of mesangial cells could lead to alterations in glomerular hemodynamics and then to glomerular injury. In this study, the effects of glucose and insulin on the contractile response of cloned homogeneous cultures of rat glomerular mesangial cells to angiotensin II were examined. Cells were cultured in normal-glucose medium (D-glucose at 200 mg/dl) and normal-glucose medium with added insulin (4 microgram/ml). To mimic the diabetic state, cells were cultured in high-glucose medium (D-glucose at 550 mg/dl) and high-glucose medium with added insulin. The media contained 20% fetal calf serum. Cells were grown for at least 1 wk in medium prior to contraction experiments. All clones of mesangial cells grown in the presence of additional insulin, in either normal- or high-glucose media, underwent contraction when treated with angiotensin II (0.001-10 microM). Seventy-five percent of the cells contracted. Not one contracted cell was seen in cultures grown without insulin in the medium, even when exposed to 10 microM angiotensin II. From these data, it appears that insulin may be required for the contractile response of mesangial cells to angiotensin II. Loss of contractile activity by mesangial cells in low- or no-insulin conditions (e.g., juvenile diabetes mellitus) could lead to a marked increase in glomerular blood flow, ultimately resulting in glomerulosclerosis.

Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation.

Micropuncture studies were performed in three groups of male Munich-Wistar rats 1 wk after surgery: group I, eight control rats that underwent laparotomy and were fed a normal diet; group II, nine rats that underwent right nephrectomy and segmental infarction of five-sixths of the left kidney and were fed a normal diet; and group III, seven rats that underwent the same renal ablative procedure and were fed a low protein diet. Single nephron glomerular filtration rate (SNGFR) was higher in the remnant kidney of group II rats compared with group I rats due to higher average values for mean glomerular transcapillary hydraulic pressure difference (delta P) and initial glomerular plasma flow rate (QA) in group II. Glomeruli in remnant kidneys of group II showed striking alterations in morphology, including epithelial cell protein reabsorption droplets, foot process fusion, and mesangial expansion. Group III rats demonstrated a mean SNGFR not statistically different from that of group I, but significantly less than that of group II rats. This lack of absolute hyperfiltration in remnant glomeruli of group III rats relative to group I obtained because QA and delta P did not increase above values found in group I. The glomerular structural lesions seen in group II were also largely attenuated in group III. These studies demonstrate that alterations in glomerular hemodynamics associated with renal ablation are accompanied by structural lesions and suggest that sustained single nephron hyperfiltration may have maladaptive consequences by damaging remnant glomeruli.

Heavy metal-induced alterations in ion transport by turtle urinary bladder.

Previous studies of heavy metal salt-induced acute renal failure demonstrated abnormalities of fluid and solute transport by nephron segments and alterations in glomerular filtration rate and renal hemodynamics. To determine the direct effects of uranyl nitrate (UN) or HgCl2 on ion transport, their effects were studied on the isolated urinary bladder of the turtle. Unidirectional 24Na+ and 36Cl- fluxes were measured across short-circuited bladders. The addition of 0.1 mM UN to the mucosal solution resulted in a 69.9 +/- 4% (SEM) decrease in short-circuit current (SCC) without change in transepithelial resistance. Net Na+ flux (7.95 +/- 0.81 mueq/h per 8 cm2) decreased by the same magnitude as the SCC, primarily due to a 5.75 +/- 0.76 mueq/h per 8 cm2 decrease in the mucosal- (M) to-serosal (S) Na+ flux. Net Cl- flux decreased also primarily due to a decrease in M-to-S Cl- flux. Addition of 0.4 mM UN to S did not measurably affect the SCC or ion fluxes. The addition of 10 muM HgCl2 in another group of bladders reduced SCC and M-to-S Na+ flux by 81 +/- 7% without change in Cl- fluxes or resistance. The removal of either UN or HgCl2 from M by washing did not reverse the decreased SCC, but after washing addition of either dithiothreitol, 2 mM, or amphotericin B, 20 mug/ml, to M completely reversed the effects of UN or HgCl2 on SCC. These studies suggest that heavy metal salts inhibit Na+ transport by the turtle bladder without altering passive ion fluxes.