TY - JOUR
T1 - The acute kidney injury to chronic kidney disease transition in a mouse model of acute cardiorenal syndrome emphasizes the role of inflammation
AU - Matsushita, Katsuyuki
AU - Saritas, Turgay
AU - Eiwaz, Mahaba B.
AU - McClellan, Nicholas
AU - Coe, Ian
AU - Zhu, Wenbin
AU - Ferdaus, Mohammed Z.
AU - Sakai, Lynn Y.
AU - McCormick, James A.
AU - Hutchens, Michael
N1 - Funding Information:
This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases ( NIDDK) K08DK090754 (to MPH), NIDDK R01 DK098141 (to JAM), DFG German Research Foundation 332853055 , and Else Kröner-Fresenius-Stiftung 2015_A197 (to TS). This material is the result of work (by MPH) that was supported with resources and the use of facilities at the Portland VA Medical Center. The contents do not represent the views of the U.S. Department of Veterans Affairs or the U.S. Government.
Publisher Copyright:
© 2019 International Society of Nephrology
PY - 2020/1
Y1 - 2020/1
N2 - Acute cardiorenal syndrome is a common complication of acute cardiovascular disease. Studies of acute kidney injury (AKI) to chronic kidney disease (CKD) transition, including patients suffering acute cardiovascular disease, report high rates of CKD development. Therefore, acute cardiorenal syndrome associates with CKD, but no study has established causation. To define this we used a murine cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) model or sham procedure on male mice. CA was induced with potassium chloride while CPR consisted of chest compressions and epinephrine eight minutes later. Two weeks after AKI was induced by CA/CPR, the measured glomerular filtration rate (GFR) was not different from sham. However, after seven weeks the mice developed CKD, recapitulating clinical observations. One day, and one, two, and seven weeks after CA/CPR, the GFR was measured, and renal tissue sections were evaluated for various indices of injury and inflammation. One day after CA/CPR, acute cardiorenal syndrome was indicated by a significant reduction of the mean GFR (649 in sham, vs. 25 μL/min/100g in CA/CPR animals), KIM-1 positive tubules, and acute tubular necrosis. Renal inflammation developed, with F4/80 positive and CD3-positive cells infiltrating the kidney one day and one week after CA/CPR, respectively. Although there was functional recovery with normalization of GFR two weeks after CA/CPR, deposition of tubulointerstitial matrix proteins α-smooth muscle actin and fibrillin-1 progressed, along with a significantly reduced mean GFR (623 in sham vs. 409 μL/min/100g in CA/CPR animals), proteinuria, increased tissue transforming growth factor-β, and fibrosis establishing the development of CKD seven weeks after CA/CPR. Thus, murine CA/CPR, a model of acute cardiorenal syndrome, causes an AKI-CKD transition likely due to prolonged renal inflammation.
AB - Acute cardiorenal syndrome is a common complication of acute cardiovascular disease. Studies of acute kidney injury (AKI) to chronic kidney disease (CKD) transition, including patients suffering acute cardiovascular disease, report high rates of CKD development. Therefore, acute cardiorenal syndrome associates with CKD, but no study has established causation. To define this we used a murine cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) model or sham procedure on male mice. CA was induced with potassium chloride while CPR consisted of chest compressions and epinephrine eight minutes later. Two weeks after AKI was induced by CA/CPR, the measured glomerular filtration rate (GFR) was not different from sham. However, after seven weeks the mice developed CKD, recapitulating clinical observations. One day, and one, two, and seven weeks after CA/CPR, the GFR was measured, and renal tissue sections were evaluated for various indices of injury and inflammation. One day after CA/CPR, acute cardiorenal syndrome was indicated by a significant reduction of the mean GFR (649 in sham, vs. 25 μL/min/100g in CA/CPR animals), KIM-1 positive tubules, and acute tubular necrosis. Renal inflammation developed, with F4/80 positive and CD3-positive cells infiltrating the kidney one day and one week after CA/CPR, respectively. Although there was functional recovery with normalization of GFR two weeks after CA/CPR, deposition of tubulointerstitial matrix proteins α-smooth muscle actin and fibrillin-1 progressed, along with a significantly reduced mean GFR (623 in sham vs. 409 μL/min/100g in CA/CPR animals), proteinuria, increased tissue transforming growth factor-β, and fibrosis establishing the development of CKD seven weeks after CA/CPR. Thus, murine CA/CPR, a model of acute cardiorenal syndrome, causes an AKI-CKD transition likely due to prolonged renal inflammation.
KW - acute kidney injury
KW - cardiac arrest
KW - cardiorenal
KW - chronic kidney disease
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U2 - 10.1016/j.kint.2019.06.022
DO - 10.1016/j.kint.2019.06.022
M3 - Article
C2 - 31623859
AN - SCOPUS:85073500386
VL - 97
SP - 95
EP - 105
JO - Kidney International
JF - Kidney International
SN - 0085-2538
IS - 1
ER -