Abstract
Acute kidney injury (AKI) is an important risk factor for incident chronic kidney disease (CKD). Clinical studies disclose that ensuing CKD progresses after functional recovery from AKI, but the underlying mechanisms remain illusive. Using a murine model representing AKI-CKD continuum, we show angiotensin II type 1a (AT1a) receptor signaling as one of the underlying mechanisms. Male adult CD-1 mice presented severe AKI with 20% mortality within 2 weeks after right nephrectomy and left renal ischemia-reperfusion injury. Despite functional recovery, focal tubular atrophy, interstitial cell infiltration and fibrosis, upregulation of genes encoding angiotensinogen and AT1a receptor were shown in kidneys 4 weeks after AKI. Thereafter mice manifested increase of blood pressure, albuminuria and azotemia progressively. Drinking water with or without losartan or hydralazine was administered to mice from 4 weeks after AKI. Increase of mortality, blood pressure, albuminuria, azotemia and kidney fibrosis was noted in mice with vehicle administration during the 5-month experimental period. On the contrary, these parameters in mice with losartan administration were reduced to the levels shown in control group. Hydralazine did not provide similar beneficial effect though blood pressure was controlled. These findings demonstrate that losartan can reduce ensuing CKD and mortality after functional recovery from AKI.
Highlights
Because clinical studies disclose that the severer Acute kidney injury (AKI) is, the more likely CKD develops after functional recovery, we subjected the mice to renal ischemia-reperfusion injury (IRI) with different duration of warm ischemia
Periodic acid-Schiff (PAS) staining revealed significant increase of renal glomerular volume in both NX and NX+IRI groups, whereas focal interstitial fibrosis, cell infiltration and tubular atrophy were only shown in kidneys of NX+IRI groups (Fig. 2c,d)
renin-angiotensin system (RAS) activation is good for maintaining glomerular filtration and compensating the function loss, vicious cycle leading to glomerulosclerosis, interstitial fibrosis and
Summary
It is possible that pathological process remains ongoing in the repairing kidney and underlies the mechanisms for the ensuing CKD even though the clinical parameters of renal function are not apparently abnormal in patients recovering from AKI34–39. Renal tubular regeneration occurs in most models of experimental AKI, but the recovery is often incomplete depending on the severity of injury[37,38]. Reduction in renal mass and nephron number appears to be an important determinant of the ensuing CKD in AKI patients, the molecular mechanisms underlying the AKI-CKD transition remain illusive.
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