Unilateral renal ischaemia in rats induces a rapid secretion of inflammatory markers to renal lymph and increased capillary permeability.

A better understanding of the inflammatory process associated with renal ischaemia-reperfusion (IR) injury may be clinically important. In this study we examined the role of the kidney in production of inflammatory mediators by analysing renal lymph after 30 min unilateral occlusion of renal artery followed by 120 min reperfusion, as well as the effect of IR on size selectivity for proteins in both glomerular and peritubular capillaries. All measured mediators increased dramatically in renal hilar lymph, plasma and renal cortical tissue samples and returned to control levels after 120 min reperfusion. The responses were differentiated; interleukin-1ß, monocyte chemoattractant protein-1 and leptin were markedly increased in plasma before reperfusion, reflecting an extrarenal response possibly induced by afferent renal nerve activity from the ischaemic kidney. Tumour necrosis factor-α was the only mediator showing elevated lymph-to-plasma ratio following 30 min reperfusion, indicating that most cytokines were released directly into the bloodstream. The IR-induced rise in cytokine levels was paralleled by a significant increase in high molecular weight plasma proteins in both lymph and urine. The latter was shown as a 14- to 166-fold increase in glomerular sieving coefficient of plasma proteins assessed by a novel proteomic approach, and indicated a temporarily reduced size selectivity of both glomerular and peritubular capillaries. Collectively, our data suggest that cytokines from the ischaemic kidney explain most of the rise in plasma concentration, and that the locally produced substances enter the systemic circulation through transport directly to plasma and not via the interstitium to lymph.

Three-dimensional ultrasonography can detect the modulation of kidney volume in two-kidney, one-clip hypertensive rats.

As volume changes are a typical finding in the two-kidney, one-clip hypertensive rat model (2K1C), it is of interest to investigate within what time frame these volume changes occur and their relation to hypertension. Kidney volume changes in Wistar rats were measured by three-dimensional (3D) ultrasonography (USG). Clipped induced stenosis was applied to the left renal artery in 11-wk-old animals (n = 8), using age-matched nonclipped rats as controls (n = 7). Ultrasonographic recordings were made before clipping and, thereafter, weekly with corresponding systolic blood pressure and body weight measurements. The nonclipped kidney showed increased volume at week 2, 5 and 7. Three wk after clipping, clipped kidneys were smaller than the nonclipped kidneys (0.47 +/- 0.11 mL versus 1.28 +/- 0.07 mL). No difference was found between the left and right kidney in the control group at any week. Blood pressure was significantly higher in the 2K1C hypertensive group 4 weeks after clipping (201 +/- 16 versus 139 +/- 4 mm Hg) with stable blood pressure thereafter. Three-dimensional USG showed that clipping caused a decrease in kidney volume from week 3 in the clipped kidney and a volume increase in the nonclipped kidney at week 2. A significant increase in blood pressure appeared after week 4.

Differential effect of tetradecythioacetic acid on the renin-angiotensin system and blood pressure in SHR and 2-kidney, 1-clip hypertension.

The tetradecythioacetic acid (TTA) is a modified fatty acid known to exhibit pleiotropic effects. First, we compared the effect of TTA on the blood pressure in spontaneously hypertensive rats (SHR) with two-kidney, one-clip (2K1C)-hypertensive rats. Second, we examined mechanisms involved in the blood pressure reduction. TTA had minor effect on systolic blood pressure (SBP) in young SHR up to 8 wk of age. In 2K1C we confirmed the blood pressure-lowering effect of TTA (SBP: 173 +/- 4 before vs. 138 +/- 3 mmHg after TTA, P < 0.001). No effect on SBP was seen in Wistar-Kyoto rat (WKY) controls. Plasma renin activity (PRA) was low in SHR and WKY controls and TTA did not change it. PRA decreased from 22.9 +/- 1.3 to 16.2 +/- 2.2 ng.ml(-1).h(-1) (P = 0.02) in 2K1C. Plasma ANG II concentration declined from 101 +/- 3 to 81 +/- 5 fmol/l after TTA treatment (P = 0.005). In the clipped kidney, tissue ANG I concentration decreased from 933 +/- 68 to 518 +/- 60 fmol/g tissue (P = 0.001), and ANG II decreased from 527 +/- 38 to 149 +/- 21 fmol/g tissue (P < 0.001) after TTA treatment. In the nonclipped kidney, TTA did not change ANG I and moderately reduced ANG II levels. The renal blood flow response to injection of ANG II into the nonclipped kidney was blunted compared with controls and normalized with TTA treatment (10 +/- 2 before vs. 20 +/- 2%, P < 0.001). The results indicate that TTA downregulates the renin-angiotensin system in high renin animals but has no effect in low renin models.

The renal vascular response to ANG II injection is reduced in the nonclipped kidney of two-kidney, one-clip hypertension.

The ANG II receptor 1 (AT(1)R) level in the nonclipped kidney of two-kidney, one-clip hypertension (2K1C) has shown to be unchanged despite a high circulating angiotensin (ANG) II level. To examine the vasoreactive response to ANG II in this kidney, injections of ANG II into renal artery were performed 6 wk after clipping of the kidney and compared with normotensive controls. The renal blood flow (RBF) response to 2.5 ng ANG II was measured by a Transonic transit-time flowmeter, before and after indomethacin and candesartan treatment, and analyzed by a computer program. The RBF response to 5 ng arginine-vasopressin (AVP) was examined for comparison with ANG II. The mRNA for AT(1A) and AT(1B) as well as Western blotting for AT(1)R in renal resistance vessels were determined, and plasma renin activity (PRA) was measured. Systolic blood pressure was 183 +/- 4 mmHg in 2K1C rats compared with 113 +/- 1 mmHg in controls (P < 0.001). PRA was significantly increased in 2K1C animals (P < 0.05). Injection of ANG II reduced RBF with 10 +/- 2% in the nonclipped kidney and 24 +/- 3% in controls (P < 0.001). After indomethacin, the RBF response increased from 10 +/- 2 to 20 +/- 3% (P < 0.02) in 2K1C rats and from 24 +/- 3 to 34 +/- 6% in controls (P < 0.01). The doses of candesartan needed to completely inhibit RBF response to ANG II were 30 microg/kg in the nonclipped kidney and 100 microg/kg in controls (P < 0.001). Western blotting and mRNA for AT(1A) and AT(1B) in the nonclipped kidney were similar to the controls. The results indicate that despite no difference in total AT(1)R levels, functional AT(1)R is downregulated in the nonclipped kidney of 2K1C rats.