Atrial natriuretic peptide and prostacyclin synergistically mediate hyperfiltration and hyperperfusion of diabetic rats.

The relative contribution of atrial natriuretic peptide (ANP) and vasodilatory prostaglandins to hyperfiltration in Wistar rats with experimental diabetes was studied 6-8 wk after streptozocin injection. Plasma levels of immunoreactive ANP were significantly higher (P less than 0.01) in hyperglycemic diabetic (72.9 +/- 11.7 pg/ml) than in normoglycemic diabetic (44.8 +/- 8.6 pg/ml) or nondiabetic (40.0 +/- 6.8 pg/ml) rats. Blocking endogenous ANP by specific ANP-antiserum infusion reduced significantly (P less than 0.01) glomerular filtration rate (GFR) and renal plasma flow (RPF) of hyperglycemic rats compared with preinfusion values (1.23 +/- 0.06-1.02 +/- 0.04; 2.87 +/- 0.25-2.40 +/- 0.10 ml.min-1.100 g-1, respectively). However, correction of hyperfiltration and hyperperfusion was only partial (nondiabetic rats GFR 0.85 +/- 0.07; RPF 2.27 +/- 0.13 ml.min-1.100 g-1). Because diabetic rats with hyperglycemia also had an increased urinary excretion of prostacyclin metabolite 6-keto-prostaglandin F1 alpha (220.6 +/- 62.8 ng/24 h) compared with nondiabetic rats (51.2 +/- 2.7 ng/24 h), we wondered whether excessive prostacyclin formation contributed to hyperfiltration and hyperperfusion in this setting. Indomethacin infusion partially reduced GFR (1.25 +/- 0.07 to 1.06 +/- 0.07 ml.min-1.100 g-1, P less than 0.05) and RPF (2.85 +/- 0.11 to 2.46 +/- 0.12 ml.min-1.100 g-1, P less than 0.01) in diabetic rats. The combined infusion of ANP antiserum and indomethacin normalized GFR and RPF in diabetic rats with hyperglycemia (1.27 +/- 0.05 to 0.88 +/- 0.05 and 2.84 +/- 0.10 to 2.22 +/- 0.06 ml.min-1.100 g-1, respectively; P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Disassociation between glomerular hyperfiltration and extracellular volume in diabetic rats

The relationship of the development of glomerular hyperfiltration in diabetes to changes in extracellular fluid volume has not been previously examined. To accomplish this task, male Wistar rats were chronically cannulated in the bladder, femoral artery and vein. Control measurements of glomerular filtration rate (GFR), renal plasma flow (RPF), extracellular fluid volume (ECF), and urinary sodium excretion were performed on two separate days prior to infusion of streptozotocin (65 mg/kg body wt i.v.). After infusion of streptozotocin, the IDDM rats were separated into two groups: untreated IDDM group of rats and IDDM rats treated with insulin at doses sufficient to normalize blood glucose (Ultralente, 2 to 8 IU/day). A third group of normal non-diabetic rats served as time controls. Measurements of renal function occurred at 1, 4, 7, 11, and 15 days after infusion of streptozotocin. Blood glucose in the non-diabetic measurement period averaged 137 +/- 30 mg/dl and increased from 412 +/- 55 after 24 hours in the untreated diabetic rats to 533 +/- 33 mg/dl after 15 days of IDDM. The time controls and the insulin-treated diabetic rats did not differ in blood glucose values at the time measurements were performed. Glomerular filtration rate increased from 1.0 +/- 0.1 to 1.7 +/- 0.1 ml/min/100 g body wt by day 15 in the untreated diabetic rats with significant increases in GFR within 24 hours. GFR of both time controls and the insulin-treated IDDM rats did not significantly vary during the time of the study. The increase in GFR in the untreated IDDM group was associated with a concomitant increase in RPF.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of weight loss on renal function in patients with severe obesity

Severe obesity is associated with increased renal plasma flow (RPF) and glomerular filtration rate (GFR). The aim of the present study was to examine whether weight loss may reverse glomerular dysfunction in obese subjects without overt renal disease. Renal glomerular function was studied in eight subjects with severe obesity (body mass index [BMI] 48.0 +/- 2.4) before and after weight loss. Nine healthy subjects served as controls. GFR and RPF were determined by measuring inulin and PAH clearance. In the obese group, GFR (145 +/- 14 ml/min) and RPF (803 +/- 39 ml/min) exceeded the control value by 61% (90 +/- 5 ml/min, P = 0.001) and 32% (610 +/- 41 ml/min, P < 0.005), respectively. Consequently, filtration fraction was increased. Mean arterial pressure, although normal, was higher than in the control group (101 +/- 4 versus 86 +/- 2 mmHg, P < 0.01). After weight loss, BMI decreased by 32 +/- 4%, to 32.1 +/- 1.5 (P = 0.001). GFR and RPF decreased to 110 +/- 7 ml/min (P = 0.01) and 698 +/- 42 ml/min (P < 0.02), respectively. Albumin excretion rate decreased from 16 microg/min (range, 4 to 152 microg/min) to 5 microg/min (range, 3 to 37 microg/min) (P < 0.01). Fractional clearance of albumin decreased from 3.2 x 10(-6) (range, 1.1 to 23 x 10(-6)) to 1.2 x 10(-6) (range, 0.5 to 6.8 x 10(-6)) (P < 0.02). This study shows that obesity-related glomerular hyperfiltration ameliorates after weight loss. The improvement in hyperfiltration may prevent the development of overt obesity-related glomerulopathy.     

Chronic renal denervation prevents glomerular hyperfiltration in diabetic rats.

BACKGROUND: The increase in glomerular filtration rate (GFR) induced by amino acid infusion is attenuated in rats with chronic renal denervation. The aim of the present study was to investigate whether renal denervation abrogates glomerular hyperfiltration occurring in the early state of diabetes mellitus. METHODS: Sprague-Dawley rats were subjected to bilateral renal denervation before induction of diabetes mellitus (DM) by streptozotocin. Clearance experiments were performed 2 weeks after onset of moderate DM. Glomerular volume was estimated following paraformaldehyde fixation in rat kidney slices from measurement of cross-sectional area of Bowman's capsule. RESULTS: GFR in non-diabetic rats with intact nerves (CON-INN) was 0.82+/-0.03 ml.min(-1).100 g(-1) body weight. Diabetic animals with innervated kidneys presented a significant glomerular hyperfiltration (1.13+/-0.03 ml.min(-1).100 g(-1) body weight), while renal denervation in diabetic rats lowered GFR towards levels of CON-INN (0.88+/-0.03 ml.min(-1).100 g(-1) body weight). Estimated glomerular volume amounted to 0.69+/-0.03.10(6) micro m(3) in the CON-INN group and was significantly higher in diabetic animals with intact renal nerves (0.86+/-0.04.10(6) microm(3)). Interestingly, renal denervation prevented the glomerular enlargement due to DM. CONCLUSIONS: Renal nerves appear to be significantly involved in the mediation of glomerular hyperfiltration in experimental DM. If the kidney is prevented from sympathetic nerve stimulation, structural changes due to early diabetic nephropathy, i.e. glomerular enlargement, are abolished.     

Glomerular response mechanisms to glycemic changes in insulin-dependent diabetics

Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured by constant inulin and PAH infusion during euglycemia and intravenous dextrose-induced moderate hyperglycemia in seven insulin-dependent diabetics with persistently elevated GFR, seven diabetics with normal GFR, and in six normal control subjects. In euglycemia, RPF was higher and calculated renal vascular resistance (RVR) lower in the hyperfiltering than the normofiltering group (P less than 0.05 for both variables), but filtration fraction (FF) was similar in all groups. During hyperglycemia, mean GFR rose significantly from 157 +/- 20 to 174 +/- 30 ml/min/1.73 m2 (11.9%; P less than 0.05) in the hyperfiltering group only. There was no statistically significant change in mean GFR in the normofiltering diabetic (116 +/- 6 vs. 114 +/- 13 ml/min/1.73 m2) and the normal control groups (117 +/- 15 vs. 113 +/- 14 ml/min/1.73 m2). RPF and FF rose by 5.8% and 9.2%, respectively, in the hyperfiltering group only, with no change in the normofiltering or normal control groups. No change in RVR was found in any group. Total tubular sodium reabsorption was higher during euglycemia in the hyperfiltering diabetics (P less than 0.01), and rose significantly during hyperglycemia (P less than 0.05) in this group only. Overnight euglycemia did not remove the increased glomerular filtration and flow of hyperfiltering diabetics. Hyperglycemia further accentuated hyperfiltration by elevating renal plasma flow and filtration fraction.     

The outcome of non-selective vs selective nitric oxide synthase inhibition in lipopolysaccharide treated rats.

Nitric oxide (NO), generated by inducible nitric oxide synthase (NOS) following lipopolysaccharide (LPS) administration, produces renal failure through autoinhibition of glomerular endothelial NOS activity. Preadministration of selective iNOS inhibitors abolishes this effect. Although nonselective NOS inhibitors further decrease GFR, current clinical trials investigate the effect of nonselective NOS inhibition in septic patients. The goals of our study were to determine whether treatment with selective NOS inhibitors can reverse the decrease in GFR in LPS treated rats with already established renal failure and to define the outcome of LPS treated rats following nonselective NOS inhibition. Four hours following the administration of LPS (4 mg/kg), we measured creatinine clearance (CrCl) before and after the administration of either L-NIL (selective iNOS inhibitor, 3 mg every 20 minutes) or saline. Selective iNOS inhibition attenuated the decrease in blood pressure [Controls: 105 +/- 6 to 98 +/- 5, LPS: 92 +/- 5* to 83 +/- 4*, LPS + L-NIL: 88 +/- 6* to 94 +/- 6 mm Hg; *p < 0.05, vs controls (n = 6)], and reversed the decrease in GFR after LPS [Controls: 2.21 +/- 0.13 to 2.07 +/- 0.11, LPS: 0.82 +/- 0.18* to 0.66 +/- 0.22*, LPS + L-NIL: 0.76 +/- 0.15* to 1.86 +/- 0.15 ml/min; *p < 0.05 vs controls (n = 6)]. We next studied the effect of complete non-selective NOS inhibition (L-NAME 200 mg, 2 hours after LPS) on LPS treated rats. All (6/6) animals treated with both LPS and L-NAME died within 2 hours following LPS, while rats treated with either LPS, L-NAME, or LPS + L-NIL survived. Histologic studies performed in all experimental groups were unremarkable. Overnight mortality was studied using smaller doses of L-NAME. All LPS + L-NAME (10/10) and 1/10 LPS treated rats died. L-NAME, control, and LPS + L-NIL animals survived. The characteristic histologic findings in LPS + L-NAME rats were diffuse ischemic changes, most importantly acute myocardial infarction. In conclusion: Selective iN-OS inhibition might prove to have clinical application as it prevents the decrease in GFR following LPS, even after renal failure is established. Treatment with a non selective NOS inhibitor in septic patients should be reconsidered.     

Effect of L-dopa decarboxylase inhibitor benserazide on renal function in streptozotocin-diabetic rats

BACKGROUND/AIMS: Benserazide (BZD), an inhibitor of the dopamine synthesis, abolished the increase in glomerular filtration rate (GFR) following the infusion of a mixed amino acid solution. These results reveal endogenous dopamine as a mediator in the renal response to amino acids. The aim of the present study was to evaluate whether dopamine is also involved in the regulation of glomerular hyperfiltration during the early state of diabetes mellitus (DM). METHODS: Male Sprague-Dawley rats were injected with a single dose of streptozotocin (60 mg/kg i.p.) for induction of experimental DM (n = 7-8/group). Age-matched non-diabetic animals, injected with citrate buffer, served as controls (CON, n = 8/group). Clearance experiments were performed 2 weeks after induction of DM in thiopental-anesthetized rats (80 mg/kg i.p.), which were continuously infused either with BZD (30 microg/min/kg) or vehicle (VHC). RESULTS: Mean arterial blood pressure was around 110 mm Hg and did not significantly differ among the groups. GFR was 0.95 +/- 0.02 ml/min/100 g b.w. in VHC-treated CON. BZD treatment did not significantly change GFR in the CON group (0.92 +/- 0.06 ml/min/100 g b.w.). As expected, glomerular hyperfiltration was observed in diabetic rats infused with VHC (1.24 +/- 0.08 ml/min/100 g b.w.). Treatment with BZD significantly reduced the diabetes-induced increase in GFR to control levels (0.95 +/- 0.05 ml/min/100 g b.w.). CONCLUSION: Our results show that the inhibition of dopamine synthesis prevented the increase in GFR due to diabetic conditions, indicating that endogenous dopamine is involved in the regulation of DM-induced changes in renal hemodynamics.     

Renal function in mice: effects of volume expansion and angiotensin II

The present study was performed to validate a simple means for assessing renal function in anesthetized mice and to characterize the renal hemodynamic responses to acute volume expansion and how these responses are altered by concurrent angiotensin II (AngII) infusions. Inulin and para-aminohippurate clearances were used to assess GFR and renal plasma flow (RPF) in three groups of male C57Bl/6 mice anesthetized with inactin (100 mg/kg, intraperitoneally) and ketamine (10 mg/kg). To avoid the hypotension associated with repeated blood sampling, a single blood sample was taken after three timed urine collections. Renal function and mean arterial pressure (MAP) were measured under euvolemic conditions (2.5 microl/min, intravenously, n = 7) during isotonic saline volume expansion (12.5 microl/min, intravenously, n = 5) and during volume expansion with concurrent AngII infusion (5 ng/min x g, n = 5). MAP in the control group was 77 +/- 2 mmHg; volume expansion alone did not change MAP significantly (83 +/- 2 mmHg), but led to significantly greater values in both GFR and RPF (1.35 +/- 0.14 versus 1.01 +/- 0.1 ml/min x g and 11.26 +/- 1.39 versus 6.29 +/- 0.5 ml/min x g, respectively). Infusion of AngII during volume expansion led to significant elevations of MAP (100 +/- 3 mmHg, P < 0.05) and prevented the increases in GFR and RPF elicited by volume expansion (0.77 +/- 0.08 and 5.35 +/- 0.48 ml/min x g, respectively). Volume expansion also elicited marked increases in absolute and fractional sodium excretion (6.1 +/- 1.0 versus 0.62 +/- 0.2 microEq/min x g and 3.1 +/- 0.7 versus 0.4 +/- 0.1%, respectively). AngII infusion attenuated the absolute and fractional sodium excretion responses to volume expansion (3.4 +/- 1.2 microEq/min x g and 2.5 +/- 0.5%, respectively). The present findings demonstrate that anesthetized mice exhibit marked renal hemodynamic and excretory responses to isotonic saline volume expansion. Concomitant AngII infusion attenuates these responses in spite of greater increases in arterial pressure.     

L-arginine as a therapeutic tool in kidney disease

Infusion of L-arginine in experimental animals increases renal plasma flow (RPF) and glomerular filtration rate (GFR). It is likely that a component of these hemodynamic changes are mediated by nitric oxide (NO) as suggested by studies with specific antagonists of L-arginine metabolism. L-arginine administration ameliorates the infiltration of the renal parenchyma by macrophages in rats with obstructive nephropathy or rats with puromycin-induced nephrotic syndrome. L-arginine administration also blunts the increase in interstitial volume, collagen IV, and alpha-smooth muscle actin. Rats with a remnant kidney given 1% L-arginine in the drinking water had a greater GFR and RPF. L-arginine administration also decreased proteinuria. Diabetic rats given L-arginine had significantly lower excretion of protein and cyclic guanosine monophosphate than diabetic rats not receiving L-arginine. Despite persistent hyperglycemia, the administration of L-arginine prevented the development of hyperfiltration and ameliorated proteinuria in diabetic rats. In the setting of ischemic acute renal failure, the administration of L-arginine had a beneficial effect on GFR and RPF, decreased O2- production, diminished up-regulation of soluble guanylate cyclase, and prevented up-regulation of inducible NO synthase (iNOS). The pharmacokinetics of L-arginine indicate that side effects are rare and mostly mild and dose dependent.     

Beneficial effects of the urinary trypsin inhibitor urinastatin on renal insults induced by gentamicin and mercuric chloride (HgCl2) poisoning.

The authors investigated the protective effects of the urinary trypsin inhibitor urinastatin on acute renal failure induced in rats by gentamicin (240 mg/kg body weight i.p. for 3 days) and by mercuric chloride (3 mg/kg s.c.). In rats injected with gentamicin, glomerular filtration rate (GFR), renal plasma flow (RPF), and percent fractional sodium excretion (%FENa) were 151 +/- 51 microliters/min/100 g body weight, 0.69 +/- 0.31 ml/min/100 g and 0.73 +/- 0.32, respectively, whereas in rats given 100,000 U of urinastatin the renal function was significantly ameliorated (GFR 318 +/- 43 microliters/min/100 g RPF 1.41 +/- 0.35 ml/min/100 g), although the %FENa (0.46 +/- 0.26) was not significantly improved. A 50,000-unit dose of urinastatin prevented the deterioration of renal function to some extent following administration of gentamicin: GFR 219 +/- 66 microliters/min/100 g and RPF 0.93 +/- 0.43 ml/min/100 g. In the study using mercuric chloride, treatment with 75,000 U of urinastatin protected the kidney from HgCl2 poisoning, yielding values of 294 +/- 93 microliters/min/100 g (GFR), 1.03 +/- 0.41 ml/min/100 g (RPF), and 1.44 +/- 0.72 microliters/min/100 g (%FENa) as compared with respective values of 169 +/- 48 microliters/min/100 g, 0.7 +/- 0.18 ml/min/100 g, and 2.22 +/- 1.35 in the untreated rats. Renal histology revealed mild to moderate tubular epithelial changes in untreated rats, but preservation of an almost normal tubular structure in urinastatin-treated rats in both studies.     

Effect of insulin therapy on renal hemodynamic response to amino acids and renal hypertrophy in non-insulin-dependent diabetes.

Since renal hemodynamic disturbances are important in renal injury and are exacerbated by elevated plasma amino acid concentrations in insulin-dependent diabetes, we measured glomerular filtration rate (GFR) and renal plasma flow (RPF) after an overnight fast and during amino acid infusion in 12 patients with NIDDM and nine normal subjects. In the diabetic patients (plasma glucose 12.4 +/- 0.6 mmol/liter), the fasting GFR (113 +/- 6 vs. 98 +/- 7 ml/min.1.73 m2 in normal subjects, P = 0.056) and RPF (635 +/- 37 vs. 540 +/- 20 ml/min.1.73 m2 in normal subjects, P less than 0.05) were increased. After amino acid infusion, the increase in GFR (159 +/- 7 vs. 121 +/- 6 ml/min.1.73 m2 in normal subjects, P less than 0.05) and RPF (970 +/- 51 vs. 700 +/- 18 ml/min.1.73 m2 in normal subjects, P less than 0.05) were augmented. Insulin infusion for 36 hours did not change these responses. After three weeks of insulin therapy (plasma glucose 5.9 +/- 0.2 mmol/liter), the amino acid-stimulated GFR (143 +/- 5 ml/min.1.73 m2) and RPF (836 +/- 30 ml/min.1.73 m2) declined (P less than 0.05), while the fasting values remained unchanged. The right kidney volume was measured by ultrasonography and found to decrease after three weeks of insulin therapy from 188 +/- 12 to 165 +/- 9 ml/1.73 m2 (P less than 0.05). However, both values were greater than that in the normal subjects, 124 +/- 13 ml/1.73 m2 (P less than 0.01). Glomerular hyperfiltration and hyperperfusion became augmented during hyperaminoacidemia in our NIDDM patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Immune complex effects on glomerular eicosanoid production and renal hemodynamics

We examined the effect of glomerular immune complex (IC) deposition on glomerular eicosanoid synthesis and the role of the eicosanoids in glomerular pathophysiology. Rats received daily 10 mg i.v. injections of native bovine gamma-globulin (NBGG) or cationic bovine gamma-globulin (CBGG) for 21 days; age-matched controls were maintained. Immunofluorescence and electron microscopy showed mesangial deposits of IC in the NBGG group and capillary wall deposits in the CBGG group, without light or electron microscopic evidence of leukocyte infiltration. One week after the last antigen dose, GFR was similar in all three groups, but RPF increased in the rats given CBGG; (8.37 +/- 0.90 vs. control 5.54 +/- 0.56 ml/min, P less than 0.05). Glomerular synthesis of prostaglandin E2 (PGE2) and thromboxane B2 (TxB2) was normal in animals that received NBGG. Rats given CBGG had increased glomerular production of PGE2, (2.23 +/- 0.37 vs. control 1.03 +/- 0.16 ng/mg glomerular dry wt, P less than 0.05) and TxB2 (3.12 +/- 0.50 vs. control 0.48 +/- 0.07 ng/mg glomerular dry wt, P less than 0.001). Proteinuria only developed in the rats given CBGG, 86.6 +/- 18 mg/24 hr, which correlated with glomerular TxA2 synthesis, r = 0.82, P = 0.01. Acute administration of the TxA2 synthesis inhibitor, UK-38,485, and a TxA2 receptor antagonist, EP-092, to rats given CBGG did not affect GFR or RPF. The cyclo-oxygenase inhibitor, indomethacin, reduced both GFR and RPF by up to 40% in CBGG-immunized rats. Oral administration of UK-38,485 for six days to nephrotic rats did not result in a statistically significant reduction of proteinuria despite 85% inhibition of glomerular TxB2. We conclude that cationic antigen induces a glomerular disease pathologically similar to membranous nephropathy. The increment of RPF is most probably due to increased glomerular PGE2. The increased TxA2 has no effect on glomerular hemodynamics and probably is not a component in the pathogenesis of proteinuria.     

Reversal of glomerular hyperfiltration and renal hypertrophy by blood glucose normalization in diabetic rats

Two groups of rats with streptozocin-induced diabetes and one group of nondiabetic control rats were studied. Group 1 diabetic rats received daily insulin to maintain blood glucose levels at 300-400 mg/dl for 44 wk. Group 2 diabetic rats received the same insulin regimen for 37 wk and then received an increased dose of insulin to return blood glucose levels close to normal for 7 wk. Group 3 nondiabetic rats were age-matched controls. Glomerular filtration rate (GFR) and kidney weight were elevated in moderately hyperglycemic group 1 rats compared with group 3 rats. Normalization of blood glucose returned both GFR (group 1, 1.83 +/- 0.04 ml/min; group 2, 1.36 +/- 0.05 ml/min; group 3, 1.45 +/- 0.07 ml/min) and kidney weight (group 1, 2.55 +/- 0.06 g; group 2, 1.82 +/- 0.05 g; group 3, 1.72 +/- 0.06 g) to normal in group 2 rats. Despite a sustained increase in GFR, group 1 rats did not exhibit any increase in glomerular volume (group 1, 2.77 +/- 0.09 x 10(6) microns3; group 2, 2.69 +/- 0.09 x 10(6) microns3; group 3, 2.81 +/- 0.7 x 10(6) microns3). Group 1 rats did, however, exhibit a significant increase in glomerular mesangial volume (group 1, 0.31 +/- 0.02 x 10(6) microns3; group 2, 0.28 +/- 0.02 x 10(6) microns3; group 3, 0.21 +/- 0.01 x 10(6) microns3), which was not reversed by normalization of blood glucose in group 2. These findings show that normalization of blood glucose can reverse established glomerular hyperfiltration and renal hypertrophy in moderately hyperglycemic diabetic rats. They further indicate that mesangial expansion is associated with sustained moderate hyperglycemia in this disease model.     

Protein intake and blood glucose as modulators of GFR in hyperfiltering diabetic patients.

Glomerular hyperfiltration has been claimed to be a risk factor for the development of diabetic nephropathy. Protein intake and hyperglycemia can both increase GFR in diabetic and normal subjects. Our study was designed to explore the relative importance of short-term changes in protein intake and glycemia on the modulation of renal hemodynamics in insulin-dependent diabetic (IDDM) patients with and without glomerular hyperfiltration. The renal hemodynamic response to a protein challenge was studied in eight hyperfiltering (HF) and eight normofiltering (NF) patients after a three week period of low or normal protein diet (LPD, NPD), each study being conducted twice, in random order, under conditions of prevailing hyperglycemia (H) and euglycemia (E). In HF patients GFR failed to increase significantly in response to protein challenge during NPD under conditions of either H or E (Baseline vs. 2 hr H: 151 +/- 4 vs. 155 +/- 6, NS; E 147 +/- 4 vs. 157 +/- 7 ml/min/1.73 m2, NS). A more normal response was restored following LPD with GFR increasing in all but one patient after challenge during H and in all patients during E (Baseline vs. 2 hr H: 130 +/- 7 vs. 145 +/- 8, P less than 0.07; E: 127 +/- 7 vs. 143 +/- 7 ml/min/1.73 m2, P less than 0.01). Changes in RPF paralleled the changes in GFR and filtration fraction remained stable under all study conditions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Rosiglitazone improves glomerular hyperfiltration, renal endothelial dysfunction, and microalbuminuria of incipient diabetic nephropathy in patients

Microalbuminuria, an early feature of diabetic nephropathy, indicates intrarenal endothelial damage. In type 2 diabetes, microalbuminuria is strongly related to insulin resistance. We therefore investigated whether rosiglitazone, an insulin-sensitizing drug that is known to improve endothelial dysfunction, was able to improve intrarenal endothelial dysfunction and microalbuminuria. Nineteen type 2 diabetic patients participated in this double-blind cross-over trial. Nine patients with newly diagnosed disease without microalbuminuria were randomized to a treatment with rosiglitazone or nateglinide, each for 12 weeks. Ten patients with microalbuminuria were randomized to rosiglitazone or placebo, each for 12 weeks in addition to their previous antidiabetic medication. After each treatment, glomerular filtration rate (GFR), renal plasma flow, and filtration fraction were measured before and after blockade of nitric oxide (NO) by intravenous administration of N-monomethyl-L-arginine-acetate (L-NMMA). Ten healthy subjects served as control subjects. Type 2 diabetic patients at baseline showed glomerular hyperfiltration compared with healthy control subjects. Rosiglitazone reduced elevated GFR and filtration fraction toward control primarily in patients with microalbuminuria (GFR: 133.4 +/- 9.8 vs. 119.6 +/- 8.7 ml/min; filtration fraction: 23.2 +/- 1.7 vs. 20.5 +/- 1.6% before and after rosiglitazone, respectively; control subjects: GFR 111.7 +/- 8.6 ml/min, filtration fraction 20.4 +/- 1.5%). Rosiglitazone improved intrarenal NO bioavailability in type 2 diabetes toward control as shown by infusion of L-NMMA. Rosiglitazone reduced albumin excretion in type 2 diabetes with microalbuminuria from 116.5 +/- 31 to 40.4 +/- 12 mg/day. Rosiglitazone ameliorated glomerular hyperfiltration in early type 2 diabetes, improved NO bioavailability, and lessened renal end-organ damage in type 2 diabetes with microalbuminuria.     

Renal kallikrein and hemodynamic abnormalities of diabetic kidney.

The relationship between renal hemodynamic abnormalities and renal kallikrein activity was studied in streptozocin-induced diabetic rats. Diabetic rats were either not treated with insulin and had plasma glucose levels greater than 400 mg/dl (severely hyperglycemic diabetic [SD]) or were treated with 1.5-1.75 U/day protamine zinc insulin and had glucose levels of 200-300 mg/dl (moderately hyperglycemic diabetic [MD]). In SD rats, kidney tissue level and excretion of active kallikrein were reduced after 3 wk compared with age-matched nondiabetic control rats (tissue, 11.7 +/- 1.9 vs. 20.5 +/- 1.8 ng/mg protein, P less than 0.005; urine, 126 +/- 12 vs. 179 +/- 10 micrograms/24 h, P less than 0.005). Despite increased kidney size, renal plasma flow (RPF) was reduced in SD rats (5.38 +/- 0.23 vs. 6.37 +/- 0.20 ml/min, P less than 0.05). Glomerular filtration rate (GFR) was not significantly lower (2.77 +/- 0.60 vs. 3.02 +/- 0.56 ml/min). In MD rats, kidney tissue level and excretion of active kallikrein were increased after 5 wk compared with age-matched nondiabetic control rats (tissue, 28.4 +/- 1.3 vs. 23.3 +/- 1.7 ng/mg protein, P less than 0.05; urine, 289 +/- 16 vs. 196 +/- 13 micrograms/24 h, P less than 0.001). In MD rats, GFR and RPF were increased (3.80 +/- 0.11 and 8.04 +/- 0.17 ml/min, respectively) compared with control rats (3.22 +/- 0.05 and 7.28 +/- 0.09 ml/min, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Glomerular hemodynamics and hormonal participation on cyclosporine nephrotoxicity

The mechanism of cyclosporine A (CyA) nephrotoxicity is unclear. In order to evaluate renal microcirculation seven euvolemic Munich-Wistar (MW) rats were studied after acute CyA treatment (50 mg/kg, i.v.). Both total glomerular filtration rate (GFR, 0.96 +/- 0.04 vs. 0.47 +/- 0.07 ml/min) and single nephron GFR (27.90 +/- 3.39 vs. 14.02 +/- 3.49 nl/min) declined significantly (P less than 0.001). It was observed an increase in afferent (RA, increases 188%) and efferent (RE, increases 360%) arteriolar resistances that caused a decrease on glomerular plasma flow rate (QA) from 100.99 +/- 17.09 to 44.37 +/- 13.37 nl/min (P less than 0.001). Mean glomerular capillary hydraulic pressure (PGC) increased from 45 +/- 1 to 55 +/- 4 mm Hg (P less than 0.05) and the glomerular ultrafiltration coefficient (Kf) decreased by 70% (0.096 +/- 0.030 to 0.031 +/- 0.010 nl/sec X mm Hg, P less than 0.05). Additionally, in order to study hormonal participation in this nephrotoxicity, other three groups of MW rats were previously treated with captopril (2 mg/kg, i.v.), verapamil (20 micrograms/kg/min, i.v.) or indomethacin (2 mg/kg, i.v.). Both captopril and verapamil minimized the renal effects of CyA, with a decline of approximately 25% instead of approximately 50% on GFR and RPF. Moreover, two groups of Brattleboro rats were studied. Acute CyA administration in homozygote Brattleboro rats produced a decline of only approximately 22% and approximately 31%, respectively, in GFR and renal plasma flow (RPF), when compared with MW rats (P less than 0.05). Similar results were observed in heterozygote Brattleboro rats when compared with MW rats, disclosing differences due to a different strain of rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Endothelin receptor antagonism is protective in in vivo acute cyclosporine toxicity.

Endothelin (Et) has been implicated in cyclosporine A (CsA) nephrotoxicity. We have previously shown that CsA treatment in rats results in up-regulation of Et receptors specifically within the kidney. The role of Et in vivo CsA nephrotoxicity was therefore studied further with a new competitive antagonist, BQ-123, specific for Et(A) receptors (EtRA). Systemic administration of CsA in Munich-Wistar rats resulted in marked glomerular hypoperfusion and hypofiltration, with RPF in left and right kidneys falling by some 40% to 1.60 +/- 0.25 and 1.73 +/- 0.38 ml/min and GFR decreasing by some 20% to 0.61 +/- 0.05 and 0.67 +/- 0.11 ml/min, respectively. Selective infusion of EtRA into the left renal artery following systemic CsA treatment had no effect on this hemodynamic pattern (RPF 1.58 +/- 0.29 and 1.92 +/- 0.34 ml/min and GFR 0.60 +/- 0.09 and 0.70 +/- 0.08 ml/min in left and right kidneys, respectively, P = NS vs. CsA period). By contrast, intrarenal infusion of EtRA prior to systemic administration of CsA resulted in a strikingly different pattern of renal hemodynamics. Thus, EtRA pretreatment in the left kidney protected against glomerular dysfunction following CsA: RPF was maintained, 3.23 +/- 0.28 ml/min versus 2.96 +/- 0.31 (P = NS EtRA vs. EtRA + CsA), as was the GFR, 1.04 +/- 0.16 ml/min versus 1.12 +/- 0.09 (P = NS). However, the contralateral right kidneys of these rats, not pretreated with EtRA, showed no protective effect: RPF decreased from 3.15 +/- 0.34 ml/min to 2.39 +/- 0.19 and GFR from 1.04 +/- 0.10 ml/min to 0.85 +/- 0.07 (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Selective inhibition of inducible nitric oxide synthase enhances intraglomerular coagulation in chronic anti-Thy 1 nephritis

BACKGROUND: A particular Lewis rat substrain (LEW/Maa) develops chronic glomerulonephritis in the anti-Thy 1 model (aThy 1-GN) characterized by increased microaneurysm formation, chronic glomerular sclerosis and persistent albuminuria. This phenotype is accompanied by increased and prolonged glomerular induction of inducible nitric oxide synthase (iNOS) when compared to the LEW/Moe substrain, in which aThy 1-GN resolves quickly. We investigated the effect of selective iNOS inhibition by l-N6-(1-iminoethyl)-lysine (L-NIL) administration on aThy 1-GN in LEW/Maa rats. METHODS: Nephritic rats were studied over a period of 7 days. L-NIL-treated animals received 20 mg/day L-NIL in the drinking water starting two days prior to disease induction. iNOS activity was determined in cultured glomeruli and in urine samples, respectively. Severity of aThy 1-GN was determined by scoring glomerular matrix expansion and microaneurysm formation, and by albuminuria measurements (ELISA). Immunohistochemical evaluation was performed including staining for macrophages (ED-1), platelets (PL-1) and fibrin deposition. RESULTS: L-NIL treated rats (+NIL) showed a significant decrease in peak nitrate production by ex vivo cultured glomeruli, and in urinary nitrate excretion versus untreated nephritic rats (-NIL). Mean arterial pressure remained unchanged in both +NIL and -NIL rats. +NIL rats developed significantly increased albuminuria (+44%) associated with a significant increase in glomerular platelet (+45%) and fibrin deposition (+48%). CONCLUSIONS: Selective inhibition of iNOS aggravated albuminuria in chronic aThy 1-GN in LEW/Maa rats. Induction of iNOS during the inflammatory phase of this model may be a partially protective mechanism by interfering with intraglomerular coagulation processes.     

Effect of nifedipine and captopril on glomerular hyperfiltration in normotensive man.

Glomerular hyperfiltration and hypertension induced by extensive loss of renal parenchyma are suspected to accelerate progression of renal failure. Amino acid infusion or protein ingestion also modify renal hemodynamics and increase glomerular filtration rate (GFR). This phenomenon was used to study the influence of two commonly used antihypertensive agents, captopril and nifedipine, on renal hemodynamics at rest and during glomerular hyperfiltration. Thirteen healthy volunteers were studied on three separate days (days A, B, and C) in random sequence: inulin and p-amino hippurate (PAH) clearance were measured first under glucose infusion and afterwards under stimulation by amino acid infusion (0.35 mmol/kg/min; 4 mg/kg/min). Day A served as a control, where no medication was given. On day B, 10 mg nifedipine, and on day C, 25 mg captopril, were administered orally before study. Without premedication (= day A, control) GFR increased from 108.0 +/- 6.9 mL/min (SEM) to 131.7 +/- 7.0 mL/min (P less than 0.05). On day B (nifedipine), GFR before stimulation by amino acids was already elevated to 121.8 +/- 4.2 mL/min (P less than 0.05 compared with day A) and increased to 132.6 +/- 6.3 mL/min with infusion of amino acids, thus to the same range as on day A without medication. On day C, after captopril, GFR did not increase with infusion of amino acids (from 112.5 +/- 7.2 to 117.3 +/- 6.3 mL/min). Our results indicate the calcium channel antagonist nifedipine and the angiotensin-converting enzyme (ACE) inhibitor captopril differ in their effect on intrarenal hemodynamic parameters. Nifedipine induces hyperfiltration at rest and allows maximal hyperfiltration to develop under amino acid infusion.(ABSTRACT TRUNCATED AT 250 WORDS)