Uremic toxins induce free radical production by renal tubular cells and activate NF-kappaB which, in turn, up-regulates PAI-1 expression. Thus, progression of chronic renal failure may be promoted by PAI-1 up-regulation induced by uremic toxins.

In Munich-Wistar rats, a micropipette was inserted into a first-order branch of the left main renal artery and continuously infused with human/porcine endothelin (0.4 ng/min). Micropuncture measurements revealed substantial differences within the cortical microcirculation of the same left kidney: SNGFR was some 35% lower in glomeruli exposed to endothelin compared with non-endothelin-perfused glomeruli (P < 0.005). Similarly, glomerular plasma flow rate was some 38% lower in the endothelin-exposed glomeruli (P < 0.001). The hypoperfusion and hypofiltration in the endothelin-exposed glomeruli reflected an increase in resistances in the afferent and efferent arterioles. There was no difference in the value of the glomerular capillary ultrafiltration coefficient between the two populations of glomeruli.We also studied kidneys that underwent 25 min of renal artery clamping 48 h before study. Antiendothelin antibody infused into one of the branches of the main renal artery ameliorated the vasoconstriction characteristic of postischemic nephrons: within the cortical microcirculation, the SNGFR in glomeruli exposed to antiendothelin antibody was 27.0±3.1 nl/min as compared with 17.4±1.7 measured in glomeruli not perfused with the antibody (P < 0.001). Similarly, glomerular plasma flow rate was higher in the glomeruli exposed to antiendothelin antibody (128.7±14.4 nl/min vs. 66.6±5.6, P < 0.005). Resistances in both the afferent and efferent arterioles were substantially lower in the antibody-exposed glomeruli. It is, therefore, suggested that endothelin, presumably released from damaged endothelium, may play an important intermediary role in the hypoperfusion and hypofiltration observed in postischemic kidneys. Introduction Vasomotor tone is controlled by dynamic interplay of neurogenic and myogenic mechanisms and circulating hormones. In the last several years, evidence has accumulated that the endothelium elaborates both vasoconstrictive and vasodilative substances, thereby participating in this dynamic regulation of vascular tone MethodsAll experiments were done in male Munich-Wistar rats weighing 180-230 g. The animals were allowed access to standard rat chow and tap water until the day ofthe experiment. Group 1 animals consisted of seven normal rats. The animals were prepared for micropuncture as previously described (4-6). Briefly, under anesthesia (70 mg Inactin/kg body wt i.p.; BYK, FRG) tracheostomy was performed and indwelling polyethylene catheters were inserted into the femoral artery and vein and jugular vein for blood sampling, monitoring of systemic blood pressure, infusion of plasma, and inulin as previously described (4-6). In addition, one ofthe main branches ofthe left main artery was gently isolated. Care was taken not to disrupt the renal nerves and lymphatics. This branch vessel was momentarily (< 5 s) occluded with fine forceps and distribution of its blood flow was marked on the surface of the kidney with a permanent ink marker by noting the blanching of the kidney surface. Using micro...

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CS-045 is a new oral antidiabetic agent that was effective in insulin-resistant diabetic animal models, including the KK mouse, the ob/ob mouse, and the Zucker fatty rat. CS-045 was not effective in the streptozocin-treated mouse, an insulin-deficient diabetic animal model. In fed KK mice, CS-045 lowered the plasma glucose levels in a dose-dependent manner after a single oral administration, and the hypoglycemic effect lasted for at least 18 h. In normal rats, however, plasma glucose levels were not changed after administration of CS-045. CS-045 when given chronically (2 wk) to diabetic KK and ob/ob mice as a 0.2% food admixture dramatically improved hyperglycemia, hyperinsulinemia, and hypertriglyceridemia to near-normal values and decreased plasma lactate, free fatty acid, and ketone body levels without reducing food intake or body weight. In the obese Zucker fatty rat, oral administration of CS-045 had a similar effect in lowering plasma glucose, insulin, triglyceride, free fatty acid, lactate, and ketone body levels. The CS-045-treated Zucker fatty rats showed increased glucose tolerance and decreased insulin secretion in response to oral glucose. After 9 days of treatment, insulin binding to adipocyte plasma membranes from both CS-045-treated Zucker fatty rats and KK mice was increased. Furthermore, 2-deoxyglucose uptake in CS-045-treated adipocytes was increased and the insulin dose-response curve was shifted to the left. These findings suggest that CS-045 increases not only insulin sensitivity but also insulin responsiveness. Based on its pharmacological profile, CS-045 is a new orally effective antidiabetic agent that may reduce abnormalities of glucose and lipid metabolism in obese and non-insulin-dependent diabetes mellitus patients with insulin resistance.

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We studied the effect on the progression of glomerular sclerosis of two different experimental maneuvers, peritoneal dialysis and oral adsorbent, which remove circulating substances in different fashions. Munich-Wistar rats with established glomerular sclerosis, verified by renal biopsy analysis at seven weeks after subtotal nephrectomy, were treated for four weeks with either peritoneal dialysis (PD) or oral charcoal adsorbent (AST-120). Treatment was initiated at eight weeks. Rats were paired in treatment and control groups according to the similarity in the degree of sclerosis determined at biopsy with a minimum of 50 glomeruli analyzed. Systolic blood pressure and BUN and creatinine clearance, measured at seven to eight weeks, were not different among groups. In Group 2 rats, PD was performed with 1.5% dextrose for eight one-hour cycles, six days per week, while Group 1 control rats had zero indwelling time of the dialysate. Group 4 rats received AST-120, an oral adsorbent charcoal, mixed 5% by weight with standard rat chow and given ad libitum from 8 to 12 weeks after subtotal nephrectomy, while control Group 3 rats received only rat chow. Whole kidney GFR at 12 weeks was significantly higher in Group 2 PD versus Group 1 control (0.50 +/- 0.08 vs. 0.30 +/- 0.05 ml/min, P less than 0.05). There was no statistical difference for BUN and whole kidney creatinine or inulin clearance in Group 4 AST-120 treated versus Group 3 control rats. Light microscopic studies in autopsy specimens revealed that both PD and AST-120 attenuated progression of glomerular sclerosis.(ABSTRACT TRUNCATED AT 250 WORDS)

To explore the mechanism of glomerular permselectivity defect in passive Heymann nephritis, an experimental model of human membranous glomerulopathy, Munich-Wistar rats were subjected to both micropuncture assessment of glomerular hemodynamics and whole kidney clearance measurements of graded size dextrans 10 days after injection of sheep anti-rat tubular antigen (anti-Fx1A). Compared with normal control rats, anti-Fx1A-treated animals were characterized by marked proteinuria (65 +/- 8 micrograms/min versus 6 +/- 1, p less than 0.001), markedly and significantly higher glomerular transcapillary hydraulic pressure difference (40 +/- 1 mm Hg versus 33 +/- 1, p less than 0.001), depressed ultrafiltration coefficient and impaired glomerular size-selective function as determined by fractional clearance of dextrans. Calculation of membrane parameters based on a recently defined heteroporous membrane model revealed abnormally high availability of non-size selective, large pore pathways in the glomerular capillary wall of the rats with passive Heymann nephritis. To ascertain the role of the altered hemodynamic pattern in the observed defect in the size-selective function of the glomerular capillary wall, glomerular transcapillary hydraulic pressure difference was manipulated experimentally in these proteinuric rats by intra-aortic infusion of acetylcholine or angiotensin II. These agents respectively suppressed and augmented glomerular transcapillary hydraulic pressure difference and brought about a decline of and a further rise in fractional clearance of larger dextrans along with parallel changes in both urine protein excretion rate and availability of nonselective channels. These results indicate that the permselectivity defect in passive Heymann nephritis is attributable, at least in part, to impaired size selectivity of the glomerular capillary wall caused by a prevailing abnormally high transcapillary hydraulic pressure difference.

A partial renal vein constriction (RVC) was induced acutely in Munich-Wistar rats. RVC caused a marked reduction in glomerular plasma flow rate, and rises in glomerular transcapillary hydraulic pressure difference and efferent arteriolar resistance. These changes were associated with a marked increase in urinary protein excretion, on average from a baseline level of 8 to approximately 120 mg/24 hrs per kidney. Infusion of saralasin, an angiotensin II (AII) antagonist, largely normalized these indices, including urinary protein excretion (to approximately 35 mg/24 hrs per kidney), despite continued RVC. In separate rats, fractional clearances of neutral [125I]dextrans (molecular radii = 18-60 A) (CDEX/CIN) were measured. RVC caused a significant increase in CDEX/CIN for large dextrans (greater than or equal to 44A), but not small dextrans (less than or equal to 42A). Saralasin infusion led to a partial return toward baseline values of CDEX/CIN for the large dextrans. On the basis of the heteroporous membrane theory for glomerular filtration, the glomerular sieving defect during RVC was attributed to an increase in the relative fluid flux through a group of large non-selective pores. A marked alteration in glomerular microcirculatory pattern induced by enhanced action of endogenous AII in turn seemed to account largely, although not entirely, for the impairment of glomerular size-selectivity during RVC.