Interferon gamma attenuates hypertensive renal injury in salt-sensitive Dahl rats.

Abstract

Evidence has been provided that the immunological mechanism is involved in the genesis or maintenance of hypertension. In the present study, we investigated the effects of interferon gamma, a potent immunomodulator derived from lymphocytes, on hypertension and organ damage in Dahl salt-sensitive rats and in spontaneously hypertensive rats. Subcutaneous injection of interferon gamma (SxlO 4 units/kg body wt once a week for 10 weeks) reduced blood pressure in Dahl salt-sensitive rats fed a 4% high salt diet (174 versus 194 mm Hg, p<0.025). This blood pressure reduction was associated with an improvement of renal functions, an increase in glomerular nitration rate (690 versus 569 ml/day/100 g body wt, p<0.05), and decreases in urinary protein excretion (48 versus 78 mg/day/100 g body wt, p< 0.025) and urinary N-acetyl-/3-D-glucosaminidase excretion (143 versus 183 milliunits/day/100 g body wt, p<0.05). Morphological investigation showed a marked resolution of the vascular injuries seen in untreated Dahl salt-sensitive rats, e.g., intimal and medial hyperplasia, with infiltration of inflammatory cells, and significant amelioration of the glomerular sclerotic changes. In contrast, interferon gamma affected neither blood pressure nor renal functions in spontaneously hypertensive rats. These data indicate that interferon gamma ameliorates the development of hypertension and vascular and renal injuries in Dahl salt-sensitive rats. The resolution of vascular and renal injuries contributes, in part, to the antihypertensive action of interferon gamma. there is an association between hypertension and immune dysfunction in humans and in experimental hypertensive animals.1 -2 The mechanism of this interrelation is not fully understood. However, since White and Grollman 3 reported the implications of autoimmunity in hypertension after renal infarct, an increasing amount of evidence has indicated that suppressor T cell dysfunctions and subsequent hyperimmunoglobulinemia or an increase in autoantibodies would bring about the vascular injuries and renal damage of a hypertensive state, both of which are supposed to contribute to the development of hypertension, particularly in its chronic phase. 4 -6 It has been demonstrated, in fact, that the periarterial spaces are infiltrated with inflammatory cells in spontaneously hypertensive rats (SHRs), and these lesions are resolved by immunosuppressive therapy.7 Moreover, the arterial damages in salt-induced hypertension could not be produced in nude mice.

Tumor Necrosis Factor-α

“…20 Administration of IFN-␥ to New Zealand white mice has been reported to increase mean arterial pressure. 21 On the other hand, administration of IFN-␥ in Dahl salt-sensitive rats has been shown to reduce blood pressure, 22 while having no effect in spontaneously hypertensive rats. 23 Such variability in the data is consistent with the postulated pathophysiological heterogeneity of hypertension among different experimental models.…”

Inhibitory Effects of a Subdepressor Dose of L-158,809, an Angiotensin II Type 1 Receptor Antagonist, on Cardiac Hypertrophy and Nephropathy Via the Activated Human Renin-Angiotensin System in Double Transgenic Mice With Hypertension

“…The infiltration of inflammatory cells to the region surrounding arterioles also occurs in other animal models with chronic hypertension, such as spontaneously hyper-tensive rats, salt-sensitive Dahl rats and DOCA-salt hypertensive rats, and it is known that an immunological abnormality is involved in this occurrence. [52][53][54][55] Renal disorders can occur by an immunological mechanism or by a nonimmunological mechanism, such as abnormal renal hemodynamics, and activation of the RAS is thought to play a major role in the latter mechanism. 56,57 In the present study, the infiltration of inflammatory cells to the region surrounding arterioles was seen in the no-dosage group with accelerated RAS, while such changes were not seen in the L-158,809 group, whose AII was inhibited without causing hypotension.…”

High Perfusion Pressure Accelerates Renal Injury in Salt-Sensitive Hypertension

“…[5][6][7][8]38 This is thought to be a consequence of predominant preglomerular vasoconstriction in the SHR that protects the glomeruli from the elevated perfusion pressure. 39,40 In contrast, reduced levels of preglomerular vasoconstriction are thought to exist in the SS rat.…”

“…Hypertension in the SHR of a magnitude and duration similar to that seen in SS rats results in little or no renal injury. [5][6][7][8] Moreover, although it is recognized that hypertension is a strong independent risk factor for renal failure, the effectiveness of BP control in the reduction of renal injury varies greatly between subpopulations of hypertensive patients. 9 -11 These observations have clouded the question of how much physical factors related to the elevation of renal perfusion pressure (RPP) actually contribute to renal injury in hypertension.…”