Involvement of Apoptosis Inhibitor of Macrophages in a Rat Hypertension Model with Nephrosclerosis: Possible Mechanisms of Action of Olmesartan and Azelnidipine

Abstract

Stroke-prone spontaneously hypertensive (SHRsp) rats develop severe hypertension resulting in renal injury. We investigated apoptosis inhibitor of macrophages (AIM) expression in nephrosclerotic rats and the involvement of AIM in olmesartan (OLM)-and azelnidipine (AZN)-induced decreases in the number of macrophages infiltrating the kidney. We randomly assigned 20-week-old male SHRsp rats to receive one of the following substances every day for 12 weeks: water (vehicle), hydralazine (HYD), OLM, or AZN. Renal damage was assessed by Masson trichrome staining. Expressions of ED-1, AIM, and oxidized low-density lipoprotein (oxLDL) were immunohistochemically detected. Apoptosis was analyzed by terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) staining. All treatment groups showed significantly less renal interstitial fibrosis than the vehicle group. AZN and OLM groups had significantly fewer AIM-expressing cells than the HYD and vehicle groups. The ratios AIM-positive cells/ ED-1-positive macrophages and TUNEL-positive cells/ED-1-positive macrophages in the AZN and OLM groups were lower and higher, respectively, than the the HYD and vehicle groups. oxLDL expression in the renal interstitium was significantly lower in treatment groups compared to vehicle group. OLM and AZN inhibited interstitial fibrosis progression in SHRsp rats by suppressing AIM expression in macrophages, followed by reducing the number of infiltrating macrophages. Key words apoptosis; macrophage; nephrosclerosis; oxidized low-density lipoproteinThe number of patients with chronic kidney disease (CKD) has increased dramatically worldwide.1) A follow-up of the National Health and Nutrition Examination Surveys in the United States reported that the frequency of CKD (stages 1-4) increased from 10.0% in 1988-1994 to 13.1% in 1999-2004. 2) CKD is an independent risk factor (heart-and kidney-related) of cardiovascular disease, and is known to increase the risks for angina pectoris, myocardial infarction, cardiac arrest, cerebrovascular disorders, peripheral vascular disease, death due to cardiovascular disease, and sudden death. 3,4) Nephrosclerosis is one of the main diseases underlying CKD.5) It involves progressive arteriosclerosis at the level of the small arteries and arterioles in the kidneys, leading to ischemic changes in the glomeruli and interstitium, consequently compromising renal function.6) This increased arteriosclerosis due to long-term hypertension associated with aging has resulted in the increased global incidence of nephrosclerosis.Previous studies have reported that macrophages play a major role in the progression of arteriosclerosis in humans and in animal models. Further, macrophage infiltration is closely associated with the onset and progression of myocardial infarction, cerebrovascular disorders, and arteriosclerotic diseases such as nephrosclerosis. [7][8][9][10][11][12] Apoptosis inhibitor of macrophages (AIM) is a secretory protein comprising 3 scavenger receptor cystein-rich...

AIM/CD5L: a key protein in the control of immune homeostasis and inflammatory disease

“…This is one of the main pathologies underlying chronic kidney disease, and it may lead to ischemic changes in the glomeruli and interstitium, consequently compromising renal function. In a rat model of nephrosclerosis, immunohistochemistry analysis showed CD5L strongly expressed in macrophages that infiltrated the diseased kidney [70]. Furthermore, treatment with drugs that inhibited kidney damage and lowered macrophage infiltration reduced CD5L expression in renal tissue, thus suggesting the that CD5L expression is critical for the progression of nephrosclerosis [70].…”

A novel approach for preventing esophageal stricture formation: olmesartan prevented apoptosis

“…Morphological and functional symptoms of progressive renal injury induced in these rats were alleviated by the inhibition of AT1R [21,22,23]. Similarly, the treatment with OLM significantly attenuated the number of TUNEL-positive cells in the animal model of progressive glomerular injury [23] and in the kidneys of hypertensive rats [24]. Moreover, in both cited studies, OLM-reduced apoptosis was associated with lower degree of interstitial fibrosis or glomerular sclerosis, respectively.…”

The Role of Renal Macrophage, AIM, and TGF-β1 Expression in Renal Fibrosis Progression in IgAN Patients

“…It suggested that AIM may have aggravated renal damage. Tadashi Uramat et al (18) established severe hypertension and induced kidney damage by using a model of spontaneous hypertension tendency (SHRsp) mice. After the treatment of hypertension with related drugs, it was found that the number of macrophages infiltrating into the glomeruli and interstitium was significantly reduced.…”

“…In recent years, there have been numerous studies on the role of AIM in renal disease. For example, Tadashi Uramat et al (18) found in the hypertensive prone mouse model that reducing the expression of AIM and oxLDL (oxidized low-density lipoprotein, which have the effect of upregulating the expression of AIM) can effectively reduce the fibrosis of renal tissue. Similarly, Megumi Oshima et al (19) found that the area of AIM and macrophage deposition in renal tissue was positively correlated with the severity of proteinuria and eGFR decrease in patients with CKD.…”