Effects of early and late antihypertensive treatment on extracellular matrix proteins and mononuclear cells in uninephrectomized SHR

Abstract

The efficacy of an early and late treatment with the angiotensin converting enzyme inhibitor lisinopril or the angiotensin II receptor blocker ICI D8731 was investigated in uninephrectomized spontaneously hypertensive rats (SHR). Rats that underwent uninephrectomy (UNX) at six weeks of age were randomly assigned to receive no treatment, lisinopril shortly after UNX, lisinopril starting 16 weeks after UNX, ICI D8731 shortly after UNX, and ICI D8731 starting 16 weeks after UNX. Blood pressure was normalized with both treatments. After six months inulin clearance was not significant different, while proteinuria and prevalence of interstitial fibrosis were significantly reduced in all treatment groups. Immunohistochemical studies revealed an interstitial, periglomerular and perivascular increase of extracellular matrix proteins in all rats, but a markedly reduced expression of collagen I, IV and fibronectin after early and late treatment compared to untreated controls. We found a significant reduction of infiltrating macrophages and T-lymphocytes in all treated animals compared to untreated controls after 2, 4 and 6 months. Especially early treatment was associated with lower numbers of infiltrating cells. Both treatments reduced proliferation of tubular and interstitial cells. There were no striking differences with regard to nephroprotection between the ACE inhibitor and angiotensin II receptor blocker. These findings show that both treatments have beneficial effects on kidney structure and function. They suggest that both ACE inhibition and angiotensin II blockade decrease renal cell proliferation and suppress the infiltration of mononuclear cells that may trigger expression of extracellular matrix proteins and progressive nephrosclerosis.

Evolution of Renal Interstitial Inflammation and NF-κB Activation in Spontaneously Hypertensive Rats

“…3). Similar increments in helper T cells were found by Geiger et al [30]although their study is not strictly comparable to ours because their protocol included uninephrectomy that would add the proinflammatory effects of renal mass reduction.…”

Positron-Emission Tomography Imaging of the Angiotensin II Subtype 1 Receptor in Swine Renal Artery Stenosis

“…We have identified the AT 1 R as a significant molecular imaging target because of its intricate involvement in the many aspects of renal physiology and pathology, [17][18][19] particularly in acute, subacute, and chronic complications of renal ischemia. 20,21 The AT 1 R is a key injury response protein because its continuing activation leads to stimulation of the extracellular matrix, 22 collagen deposition, glomerular remodeling, 23 inflammation, 24 apoptosis, 25 generation of oxygen species, and cell cycle arrest. 26 To this end, our group has synthesized several radioligands and tested them in various animal models for positronemission tomography (PET) imaging of the renal AT 1 R. [27][28][29][30][31] One particular radioligand, [ 11 C]KR31173, has shown excellent image quality in multiple animal species including nonhuman primates.…”

Angiotensin II further enhances type IV collagen production stimulated by platelet‐derived growth factor and fibroblast growth factor‐2 in cultured human mesangial cells

“…Losartan is a AT1 receptor antagonist and it inhibited the synergistic effect of Ang II, thus demonstrating that this effect is a specific effect. In vivo , the administration of ACE inhibitors and Ang II receptor antagonists to animal models of glomerulosclerosis and interstitial fibrosis have been reported to ameliorate and foreshorten the disease process 4,25,26 . In vitro , it was shown that selective antagonism of the AT1 receptor inhibits Ang II‐stimulated DNA and protein synthesis in various kinds of cultured cells 8,9,14,24 .…”