Abstract
BackgroundTo establish a model of chronic renal fibrosis following acute kidney injury (AKI) in BALB/c mice and to observe the effect of AKI on podocyte injury and chronic fibrosis of the kidney. Additional aims included using the model to explore the role of podocyte injury in AKI and post-injury fibrosis.MethodsFifty BALB/C mice were randomly divided into control group (Ctr), sham group (sham), AKI 20 group (renal ischemia, 20 min reperfusion), AKI 30 group (renal ischemia, 30 min reperfusion) and AKI 40 group (renal ischemia, 40 min reperfusion). Mice serum and 24-h urine were collected on the 8th, 9th, 10th, 14th, and 28th days for urinary protein, serum creatinine (Scr) and blood urea nitrogen (BUN) analysis. HE staining, transmission electron microscopy (TEM), Masson staining, Q-PCR, Western Blot and immunohistochemistry were applied.ResultsSerum Scr and BUN levels across all AKI groups at the 9th day were significantly higher (P < 0.05) than controls, with higher reperfusion groups maintaining that increase up to 28 days (P < 0.05). Compared with Ctr group, the urinary protein of the AKI 40 group significantly rose on the 9th day (P < 0.05), normalizing immediately on the 10th day (P < 0.05). In contrast, the AKI 30 group rose significantly on the 14th day (P < 0.05) maintaining elevated levels for two weeks (P < 0.05). HE staining demonstrated ischemia-dependent renal tissue damage was aggravated in the mild to aggravated AKI groups. Mesangial proliferation, glomerulosclerosis, and tubulointerstitial pathology were also significantly increased in these groups (P < 0.05). Masson staining further showed that glomerular, renal tubular, and interstitial collagen were increased by ischemia in a time-dependent manner. Transmission EM additionally that podocytes of the mild to severe AKI groups displayed extensive fusion, exfoliation and GBM exposure. Synaptopodin, Nephrin, and CD2AP mRNA and protein expression demonstrated ischemic time-dependent decreases, while the TRPC6 was increased. There was a significant difference in the levels of Synaptopodin, Nephrin, CD2AP, and TRPC6 between the mild and severe AKI groups (P < 0.05).Conclusions1) During the AKI process mice podocyte injury, proteinuria and the subsequent progression into chronic renal fibrosis is observed.2) Podocyte injury may be one of the causes of ischemia-reperfusion acute kidney injury and post-injury fibrosis.
Highlights
To establish a model of chronic renal fibrosis following acute kidney injury (AKI) in BALB/c mice and to observe the effect of AKI on podocyte injury and chronic fibrosis of the kidney
Biochemical and urine analysis Compared with the control group (Ctr) group, serum serum creatinine (Scr) and blood urea nitrogen (BUN) levels in the AKI 20 group, AKI 30 group, and AKI 40 group on the 9th day were significantly higher (P < 0.05)
Compared with Ctr group, urinary protein was significantly increased on the 9th day after injury in the AKI 40 group (P < 0.05), with the spike immediately diminished the day (P < 0.05) with no subsequent fluctuations
Summary
To establish a model of chronic renal fibrosis following acute kidney injury (AKI) in BALB/c mice and to observe the effect of AKI on podocyte injury and chronic fibrosis of the kidney. Chronic kidney disease (CKD), a disease involving irreversible renal dysfunction or structural damage caused by heterogeneous disease pathways [1], has become a public health issue worldwide. Delaying the progression of CKD has become one of the most important topics in the study of kidney disease. AKI can be sustained as CKD, and may even progress to end-stage renal disease (ESRD) [4]. No effective treatment measures exist to reduce tissue damage, promote repairing or prevent the occurrence of chronic fibrosis of the kidney. Preventing the progression of AKI to CKD has become the focus of much of the international kidney disease research community
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