The renin-angiotensin system as a primary cause of polyarteritis nodosa in rats

Abstract

Polyarteritis nodosa is a necrotizing vasculitis of medium-sized arteries of unknown origin. Hypertension is present in 30% of patients with polyarteritis nodosa. In those cases, high renin levels are thought to be secondary to renal involvement. The present study was performed to identify causal factors of polyarteritis nodosa. In cyp1a1ren-2 transgenic rats, vasculitis of medium-sized arteries resembling classical polyarteritis nodosa can be induced. In this model, oral administration of indole-3-carbinol (I3C) activates the liver-specific cyp1a1 promoter, leading to prorenin expression in a dose-dependent manner. After the first 6 weeks of chronic induction with 0.125% I3C, the mean arterial pressure reached a plateau of about 170 mmHg. Ten out of 11 I3C-treated rats, which were chronically instrumented with a telemetric device to measure blood pressure, developed polyarteritis nodosa within 10 weeks of I3C treatment. I3C alone or instrumentation alone did not cause polyarteritis nodosa. The angiotensin-converting enzyme inhibitor captopril completely prevented the development of polyarteritis nodosa, indicating that local angiotensin II generation is a pathogenetic factor in this model. The renin-angiotensin system can play a primary role in the development of polyarteritis nodosa in rats.

Fig 1

Effect of captopril treatment on the mean arterial pressure in cyp1a1ren-2 transgenic rats receiving indole-3-carbinol (I3C). TM: non-treated rats with transmitter, TM+I3C: I3C-treated rats with transmitter and TM+I3C+Cap: I3C-treated rats with transmitter and captopril; n= 6 per group. Time 0 marks the start of treatment with I3C and captopril, respectively. *P < 0.01 versus TM; ^§P < 0.001 versus TM+I3C.

Fig 2

Weight loss in rats with polyarteritis nodosa and its prevention by captopril. Con: untreated control rats (n= 3), TM: non-treated rats with transmitter (n= 6), TM+I3C: I3C-treated rats with transmitter (n= 6), Sham TM+I3C: sham-operated I3C-treated rats (n= 3) and TM+I3C+Cap: I3C-treated rats with transmitter and captopril (n= 6). Time 0 is the start of treatment with I3C and captopril and the initial weight of 100%, respectively. *P < 0.05.

Fig 3

Histological evidence of polyarteritis nodosa in cyp1a1ren-2 transgenic rats. Representative tissue sections of I3C-treated rats with transmitters (TM+I3C) (A) Foreign body reaction at the insertion site of the catheter (haematoxylin and eosin staining). (B) Vasculitis of a mesenteric vessel with dissection of the arterial wall and intraluminal thrombotic material (haematoxylin and eosin staining). (C) Pancreas: arterial nature of the affected vessel confirmed by Elastica van Gieson staining. (D) Fibrinoid necrosis of the endothelial wall of an intraparenchymal medium-sized renal artery; protein casts in the tubuli and intratubular protein droplets are stained orange (AFOG staining). Bar = 100 μm.

Fig 4

Identification of CD3-positive cells. (A) Immunohistochemistry of mesenteric polyarteritis lesions with anti-CD3 (DAB staining). Positively stained cells are labelled brown. (B) Chloracetate esterase reaction of mesenteric polyarteritis lesions for the identification of polymorphic leucocytes (red). Bar = 100 μm.

Fig 5

Captopril prevented the development of polyarteritis nodosa. Representative tissue sections (same magnification) of the mesenteric vessels of cyp1a1ren-2 rats (haematoxylin and eosin staining). (A) control rats, (B) I3C-treated rats (I3C), (C) I3C-treated rats with transmitter (TM + I3C), (D) transmitter-implanted rats (TM), (E) sham-operated rats treated with I3C (Sham TM + I3C) and (F) co-application of I3C and captopril to transmitter-implanted rats (TM + I3C + Cap). Bar = 250 μm.

Fig 6

Prorenin levels during the development of polyarteritis nodosa. Prorenin levels in I3C-treated rats that developed polyarteritis nodosa in a period of 10 weeks of treatment (PAN⁺) or remained unaffected (PAN^–: without captopril; PAN^– Cap: with captopril) at 3 and 6 weeks of treatment. I3C: circles (n= 6), ShamTM+I3C: crosses (n= 3), TM+I3C: triangles (n= 6) and TM+I3C+Cap: diamonds (n= 6).

Fig 7

Prevention of polyarteritis nodosa by captopril. Top: prominent nodular enlargement of mesenteric vessels (yellow arrow) of an I3C-treated rat with transmitter. The mesentery is devoid of any fat. Bottom: macroscopic normal vasculature of an I3C-treated rat with transmitter (black arrow) treated with captopril.