| Summary: | 碩士 === 國立臺灣大學 === 生理學研究所 === 104 === Evidence from many clinical studies supports that acute kidney injury (AKI) is an important risk factor for incident chronic kidney disease (CKD) and disease progression. Not only does CKD lead to end-stage renal disease (ESRD), but it also increases the risk of cardiovascular disease or even death. Clinical studies often disclose that the higher the AKI severity of a patient is, the more likely her/his kidneys progress into CKD. To this day, the mechanism underlying the incident CKD and disease progression after AKI remains illusive. We therefore conducted this study to get insight into the mechanism underlying the development and progression of CKD after functional recovery from AKI in a murine model. In our pilot study to set up a murine model of AKI-CKD continuum, we performed right uni-nephrectomy (NX) first in a group of male adult CD-1 mice. We then induced ischemia-reperfusion injury (IRI) to left kidney using non-traumatic micro-aneurysm clip to clamp renal artery with core body temperature maintained at 370C under a homeothermic blanket system 2 weeks later. Severe AKI with significant elevation of plasma levels of blood urea nitrogen (BUN) and creatinine was demonstrated 2 days after 28-minute warm ischemia and then reperfusion. Although 20% of mice died within 2 weeks after NX+IRI, functional recovery shown by the decrease of plasma BUN and creatinine to the levels seen in sham and NX control mice was observed by 4 weeks after injury. However focal tubular atrophy, increased interstitial cell infiltration and fibrosis were seen in the kidneys of mice 4 weeks after NX+IRI. Gene expression, including Col1a1, Acta2, Lcn2, Havcr1, Agtr1a and Agt which encoded collagen I 1 chain, -smooth muscle actin, neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, type 1a angiotensin II receptor and angiotensinogen respectively, was increased in the kidneys of mice 4 weeks after NX+IRI. Moreover, the systolic blood pressure (BP), urinary albumin-creatinine ratio (ACR), plasma levels of BUN and creatinine and kidney fibrosis increased in mice 5 months after NX+IRI. We then investigated the roles of hypertension and intrarenal RAS activation in the development and progression of CKD after functional recovery from AKI using the murine model of AKI-CKD continuum. Drinking water with or without type 1a angiotensin II receptor blocker losartan or direct vasodilator hydralazine was administered to NX+IRI mice from 4 weeks after injury. Mice with NX only were served as the control. Systolic BP, urinary ACR and plasma levels of BUN and creatinine were evaluated. Compared to NX group, NX+IRI mice showed acute rise of plasma BUN and creatinine on day 2 after IRI. Systolic BP, plasma levels of BUN and creatinine were not different between mice before starting different treatments at 4 weeks after IRI. During the 5-month experimental period, increase of mortality, systolic BP, urinary ACR, plasma levels of BUN and creatinine and kidney fibrosis was noted in NX+IRI group. On the contrary, these parameters in mice with losartan treatment were reduced to the levels observed in NX group. However hydralazine treatment did not provide similar protective effect even though systolic BP was controlled to the levels observed in NX group. These data suggest that kidneys do not repair completely and the CKD will progress even though the kidney function recovers initially in our murine AKI model. Intrarenal RAS activation may underlie one of the mechanisms for the subsequent CKD progression. Future studies are needed to explore the preventive effect of RAS blockade on incident CKD and disease progression in patients recovering from AKI.
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