Modulation of renal kallikrein by a high potassium diet in rats with intense proteinuria

Abstract

Injury of the renal tubulointerstitial compartment is recognized to play an important role in hypertension. Its damage may in turn, impair the activity of vasodepressor systems, like the kallikrein-kinin, in blood pressure regulation. The overload proteinuria model induces tubulointerstitial injury with activation of the renin-angiotensin system, but renal kallikrein and the development of hypertension have not received special attention. Sprague-Dawley rats received seven intraperitoneal doses of bovine serum albumin (BSA) 2 g/day under normosodic diet and were hydrated ad libitum. A second group received a high potassium diet to stimulate kallikrein production during the previous four weeks and while under BSA administration. A third one received potassium and BSA in the same schedule, but with the kinin B2 receptor antagonist, HOE140, added during the protein load phase. A control group received seven saline injections. Kallikrein protein was detected by immune labeling on renal sections and enzymatic activity in the urine. The BSA group showed massive proteinuria followed by intense tubulointerstitial damage. Blood pressure increased after the third dose in BSA animals, remaining elevated throughout the experiment, associated with significant reductions in renal expression and urinary activity of kallikrein, compared with controls. An inverse correlation was found between blood pressure and immunohistochemistry and urinary activity of kallikrein. Potassium induced a significant increase in both urinary activity and renal kallikrein expression, associated with significant reduction in blood pressure. The HOE140 antagonist blunted the antihypertensive effect of kallikrein stimulation in proteinuric rats. Loss of renal kallikrein, produced by tubulointerstitial injury, may participate in the pathogenesis of the hypertension observed in this model.

Treatment with pyrrolidine dithiocarbamate improves proteinuria, oxidative stress, and glomerular hypertension in overload proteinuria

“…We found that AO induced mild arterial hypertension. Hypertension is not a finding in female Lewis rats with AO (1) but it has been reported by other groups in SpragueDawley rats (2).…”

Antihypertensive and renoprotective effect of the kinin pathway activated by potassium in a model of salt sensitivity following overload proteinuria

“…Control experiments have shown that these inhibitors have no effect on the enzymatic activity of purified rat salivary and urinary kallikreins. Moreover, enzymatic activity obtained under these conditions was completely abolished by antiurinary kallikrein antiserum but not by nonimmune serum, indicating that the activity indeed corresponds to kallikrein activity (3,5,50). Values, expressed as milliunits per milliliters, were calculated relative to milligrams of urinary creatinine to allow for differences in volume.…”

“…The first period (induction of tubulointerstitial damage) comprised an overload proteinuria with a normosodic diet for 2 wk followed by a washout recovery period lasting another 2 wk (also with a normal sodium diet). Overload proteinuria without previous nephrectomy (to avoid the effects of renal mass reduction) was performed using one intraperitoneal injection per day for 14 days of 2 g BSA (Fraction V, A-4503; Sigma) administered as 6 ml of a 33.3% BSA solution dissolved in 0.9% sterile saline, as previously described (2,5,9,15,16).…”

“…HS, the group of rats that received protein overload followed by 2 wk of washout and 4 wk of hypersodic diet; K ϩ -HS, animals that received potassium chloride in their drinking water for 4 wk before protein overload and until the end of the experiment; K ϩ -HS-I, animals that were submitted to the same protocol as the K ϩ -HS group but where the kinin B2R antagonist icatibant was administered during the high-salt phase (4 final wk). obtained in each biopsy was used as "tubulointerstitial score," as previously published (5).…”

“…We have previously shown that massive proteinuria is associated with damage to kallikrein-producing tubules (connecting tubules) that in turn reduces tissue expression of the enzyme and lowers its urinary activity concomitant with an elevation in blood pressure. In addition, a significant antihypertensive effect was achieved when renal kallikrein synthesis was stimulated by a high-potassium diet (5).…”