The acute kidney injury to chronic kidney disease transition in a mouse model of acute cardiorenal syndrome emphasizes the role of inflammation

Abstract

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 mL/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 a-smooth muscle actin and fibrillin-1 progressed, along with a significantly reduced mean GFR (623 in sham vs. 409 mL/min/100g in CA/CPR animals), proteinuria, increased tissue transforming growth factor-b, 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.

Modeling human disease: a mouse model of acute kidney injury to chronic kidney disease progression after cardiac arrest

“…Leslie S. Gewin 1,2,3 A protective role for sirtuin 6 (Sirt6) in the context of chronic renal injury is reported by Cai et al in this issue of Kidney International. The mechanism is thought to be mediated by Sirt6's deacetylase activity, specifically on b-catenin target genes.…”

“…Sirt1 can ameliorate acute kidney injury and diabetic kidney disease and reduce fibrosis in the unilateral ureteral obstruction model. 1,2 The mechanisms by which Sirt1 is protective in CKD models include reduction of cyclooxygenase-2 and inhibition of oxidative stress, and targeting of transforming growth factor-beta (TGF-b) signaling, signal transducer and…”

“…Matsushita et al use their model to investigate type 1 CRS, the scenario in which acute cardiac dysfunction causes acute renal dysfunction. 2 Their claim that they are modeling AKI to CKD progression would also suggest this is a model of progression from type 1 to type 2 CRS (i.e., chronic cardiac dysfunction leading to chronic renal dysfunction). Hemodynamic changes, including decreased forward flow and venous congestion, are often implicated as the predominant factors driving renal dysfunction in acute heart failure.…”

A novel ultrasound-guided mouse model of sudden cardiac arrest

“…The technique described in this paper would be easily modified to allow for prolonged arrest time to study neurologic insult. Mouse SCA models have been utilized to as a clinically-relevant model of both acute kidney injury 31,32 (one day after arrest) and chronic kidney disease (seven weeks after arrest, attributed to prolonged inflammation after reperfusion) 32 . We show that our model of SCA similarly develops markers of AKI, as evidenced by elevated serum creatinine, BUN, and tubular damage 1 day after arrest (Figure 3).…”

Overexpression of SP1 restores autophagy to alleviate acute renal injury induced by ischemia-reperfusion through the miR-205/PTEN/Akt pathway

“…AKI induced by I/R has a complex pathogenesis involving innate and adaptive immune responses [10]. Studies have shown that AKI autophagy induced by I/R plays an important role in AKI in vivo and in vitro [11,12].…”