The human endothelin-1 (ET-1) gene under the control of its natural promoter was transferred into the germline of mice. The transgene was expressed predominantly in the brain, lung, and kidney. Transgene expression was associated with a pathological phenotype manifested by signs such as age-dependent development of renal cysts, interstitial fibrosis of the kidneys, and glomerulosclerosis leading to a progressive decrease in glomerular filtration rate. This pathology developed in spite of only slightly elevated plasma and tissue ET-1 concentrations. Blood pressure was not affected even after the development of an impaired glomerular filtration rate. Therefore, these transgenic lines provide a new blood pressure-independent animal model of ET-1-induced renal pathology leading to renal fibrosis and fatal kidney disease. ( J. Clin. Invest. 1997. 99:1380-1389.)
There is strong evidence for the localization of a gene responsible for diabetic nephropathy in Turkish type 2 diabetes mellitus patients. This locus maps to chromosome 18q22.3-23, between D18S43 and D18S50, an interval of 8.5 cM.
To elucidate mechanisms of angiotensin II (Ang II)-related hypertension, we infused angiotensin (76 ng/min s.c.) into rats with minipumps for 10-14 days. Control rats received sham pumps. We measured blood pressure by tail-cuff, and the excretion of aldosterone and prostaglandins (PG) (PGE 2 , prostacyclin derivative 6kPGF, a , and thromboxane [Tx] derivative TxB 2 ). Angiotensin II increased blood pressure by 20 mm Hg by day 2 and by 90 mm Hg by day 10. Aldosterone excretion increased from 10 to 70 ng/day in Ang II rats by day 7. Urine PGE 2 did not increase in angiotensin rats; however, both 6kPGF, a and TxB 2 excretion increased with angiotensin. Control rats had no changes in any of these parameters. A sympathetic component was tested in a separate group of angiotensin rats that received phenoxybenzamine (300 Mg/kg/day) during angiotensin infusion; their increase in blood pressure of 40 mm Hg at 10 days was less than in those rats with angiotensin alone but more than in control rats. Phenoxybenzamine did not influence the angiotensin-induced increases in excretion of 6kPGF la or TxB 2 . Additional groups of conscious angiotensin and control rats were equipped with splanchnic nerve electrodes on day 14 for recording of sympathetic nerve activity. Angiotensin rats had greater basal sympathetic nerve activity than the control rats. Incremental methoxamine injections demonstrated altered baroreceptor reflex function in rats receiving angiotensin. We conclude that increased blood pressure with chronic angiotensin infusion is accompanied by increased production of aldosterone and increased sympathetic tone. The latter may be modulated by PG. {Hypertension 1989;14:396-403) A ngiotensin II (Ang II) is intimately involved in / \ the homeostatic regulation of blood pres-.Z \ . sure and body fluids, although the details of its mechanisms of action remain quite controversial. 1In addition to a well-characterized vasoconstrictor action, Ang II has also been proposed to increase peripheral vascular resistance indirectly through peripheral and central mechanisms that lead to an increased activity of the sympathetic nervous system.2 -4 Further, Ang II causes sodium retention both by a direct action on the renal tubule, 5 and through the stimulation of aldosterone release. 5Finally, Ang II administration influences the plasma concentration, renal excretion, and tissue generation of prostaglandins (PGs) that modulate the vasoconstriction.6 However, the relevance of some of these studies to the pathophysiological role of Ang II in hypertension is not clear, as many were conducted during short-term Ang II infusion in animals under anesthesia.To further define mechanisms in the production of Ang II-related hypertension, we infused Ang II into conscious rats over a 14-day period. We measured sympathetic nervous system activity directly with bipolar electrodes implanted on their splanchnic nerves. We determined the excretion of aldosterone and PG (PGE2, 6kPGFi a , and thromboxane [Tx]B 2 ). To further investigate the role of the s...
The impact of gender on the course of chronic renal failure in polycystic kidney disease (PKD) has been under discussion for years. Recently an animal model of autosomal dominant PKD in the rat became available allowing this topic to be studied. The aim of this study was to evaluate disease severity according to gender, and the occurrence of anticipation and/or genetic imprinting. Male and female affected PKD rats were crossed with respective Wistar-Ottawa-Karlsburg (WOK) rats. From this P generation 26 affected F1 hybrids were obtained, which were then backcrossed with WOK rats, resulting in 275 backcrosses (BC generation). In BC rats the affected males had a significantly higher kidney weight, worse histology and poorer renal function than the females. In the male, but not the female rats of the BC generation, transmission from an affected F1 mother resulted in significantly higher kidney weight, worse histology and poorer renal function than when the gene was inherited through an affected father. Since at the same time body and kidney weight were higher in the respective unaffected males, the previous effect in the affected rats might be due to a growth factor transferred by the mother's milk. The sex of the P generation had no such impact on these parameters. Thus our data provide no evidence for disease anticipation and genetic imprinting (in the classical sense) in the PKD rats, and the assumption of a gender-dependent disease expressivity is favored.
Several rat models of polycystic kidney disease (PKD) have been published. The only rat model of autosomal dominant polycystic kidney disease currently used is the so-called Hannover rat (Han:SPRD cy/+). This model is characterized by a slow progression of uraemia, proteinuria and hyperlipidaemia. Histological changes clearly resemble those seen is human PKD. The localization of Na+/K(+)-ATPase correlating with the phenotype of the cysts--basal in moderately expanded and apical in highly expanded cysts--suggests that the mislocation of the Na+/K(+)-ATPase is involved in the mechanism of cyst expansion rather than formation, and a consequence of cell dedifferentiation rather than an initial event. Of note is a considerable gender difference in disease severity. Disease anticipation or genetic imprinting does not occur. In addition to gender, a number of interventions influence the progression rate: acceleration is noted after unilateral nephrectomy, the induction of acidosis, chloride feeding or an increased protein intake; slowing down of the course occurs after the induction of alkalosis and castration, and after treatment with lovastatin and methylprednisolone. Thus the Han:SPRD cy/+ rat represents the only well-documented rat model of autosomal dominant PKD resembling a number of features of the human disease.
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