Hypertension Accelerates The Progression Of Age-related Intrarenal Small Arterial Stiffness In The Rats

Objective: To dynamically investigate the morphological change of age-relatedintrarenal small arterial(IRSA) stiffness and the expression of Advanced glycationend-products (AGEs)、Receptor for AGEs (RAGE) in Spontaneously hypertensive rat(SHR) and Wistar-Kyoto (WKY) rats respectively, and to explore the effect of AGEsand RAGE on the progression of age-related IRSA stiffness accelerated byhypertension.Methods: SHR(n=80) and WKY rats(n=80) were respectively randomized into4-week-old group、12-week-old group、24-week-old group、48-week-old group and72-week-old group(4w,12w,24w,48w, and72w). Minimal renal vascular resistance(minRVR, slope of flow per kidney weight-pressure) was detected at each group inSHR and WKY. Morphological indexs including Medial cross-sectional areapercentage (CSA%)、 Medial thickness/external diameter(WT/ED)、 Medialthickness/short internal diameter(MT/IDshort)、Medial collagen relative area and cellproliferation index(PI) of renal arcuate arteries(RAA) and interlobular arteries (RILA)were evaluated by EVG、HE、Sirus-red staining and proliferating cell nuclear antigen(PCNA) immunohistochemical staining. Vascular smooth muscle cells(VSMCs) wasdefined by α-smooth muscle actin(α-SMA) immunofluorescent technique. Theconcentration of serum AGEs was measured by ELISA and the expression of AGEsand RAGE in RAA and RILA were assessed by immunohistochemical staining.Results:1. In WKY group, the minRVR in72w was significantly higher than that in48w(p<0.01), yet there was no obvious distinction among4to48w(p>0.05). minRVRhad shown an age-dependent increase since24w in SHR (p<0.05) and were muchhigher than that in age-matched WKY at12w、24w、48w and72w respectively(p<0.05). 2. In WKY group, All of the CSA%、MT/ED、MT/IDshortand medial collagenrelative area of RAA and RILA in72w were much higher than that in48w(p<0.01),while none of them had significant distinction aged4to48w (p>0.05). The medialcollagen relative area of RILA began to increase from12w in SHR(p <0.05),higher than that in age-matched WKY at12w、24w、48w and72w (p <0.05)respectively; however, the medial collagen relative area of RILA and the CSA%、MT/ED、MT/IDshortof both arteriola began to elevate from24w (p <0.05),maintaining a higher level than WKY at24w、48w and72w respectively(p <0.05).3. The PI of RAA and RILA in WKY first descended at12w (p <0.01) andmaintained at almost the same level among12to48w(p>0.05), then rose at72w(p<0.01). In SHR group, the PI of RAA first descended at12w (p <0.05), and thenshowed an age-dependent increase from24w(p <0.05); yet the PI of RILA hadsimilar levels between4w and12w(p>0.05) and began to progressively increasefrom24w(p <0.05). Compared to age-matched WKY rats, the PI of both arteriolain SHR were significantly higher at24w、48w and72w respectively.4. The concentration of serum AGEs and the expression level of AGEs in IRSA(1) The level of serum AGEs did not rise(among4-48w, p>0.05) until72w(significantly higher than that in48w, p<0.01) in WKY. In SHR, however, theconcentration of serum AGEs began to increase from48w(p <0.05) and weremuch higher than that in age-matched WKY at24w、48w and72w respectively(p<0.05).(2) AGEs expression in RAA media maintained at a low level at the age of4to48w(p>0.05) and elevated to a higher level in72w later(p <0.01) in WKY; unlikeRAA, the AGEs level in RILA media showed no obvious difference among4w to24w(p>0.05) and had began to increase since48w (p <0.01). The AGEs levels inboth arteriola in SHR did not until48w present a significant increase with age (p<0.01), much higher than that in age-matched WKY at48w and72w respectively(p <0.01).5. In WKY group, the RAGE level in both arteriola media had no statisticaldistinction among4w to48w(p>0.05) and72w had a higher level than48w(p <0.01). In SHR group, the RAGE level in RAA meida began to increase from24w(p <0.01) and was significantly higher than that in age-matched WKY at24w、48w and72w(p <0.05) respectively; however, the RAGE level in RILA hadpresented an age-dependent increase since12w in SHR(p <0.05), much higherthan that in age-matched WKY at12w、24w、48w and72w respectively (p <0.05).Conclusions：(1) The age-related IRSA stiffness in SHR and WKY share a commonmorphological fundation, which is the concentric remodeling of RAA and RILAmainly involving the abnormal proliferation of VSMCs and excessive collagendeposition in media(2) Hypertension accelerates the progression of age-related IRSA stiffness.Morever, hypertension to accelerate the age-related RILA stiffness may occurearlier than to accelerate the age-related RAA stiffness.(3) The elevated concentration of serum AGEs and the up-regulated expressionlevels of AGEs、RAGE in IRSA media are likely to be correlated with age-relatedIRSA stiffness in WKY and SHR; high expression level of RAGE in IRSA mediais probably contribute to the presence of hypertension accelerating age-relatedIRSA stiffness. Whether in serum or in IRSA media, the up-regulated level ofAGEs may be involved in the late stage of age-related IRSA stiffness acceleratedby hypertension.