| First Author | Yang B | Year | 2018 |
| Journal | J Am Soc Nephrol | Volume | 29 |
| Issue | 7 | Pages | 1900-1916 |
| PubMed ID | 29925521 | Mgi Jnum | J:293125 |
| Mgi Id | MGI:6436143 | Doi | 10.1681/ASN.2017050581 |
| Citation | Yang B, et al. (2018) Caspase-3 Is a Pivotal Regulator of Microvascular Rarefaction and Renal Fibrosis after Ischemia-Reperfusion Injury. J Am Soc Nephrol 29(7):1900-1916 |
| abstractText | Background Ischemia-reperfusion injury (IRI) is a major risk factor for chronic renal failure. Here, we characterize the different modes of programmed cell death in the tubular and microvascular compartments during the various stages of IRI-induced AKI, and their relative importance to renal fibrogenesis.Methods We performed unilateral renal artery clamping for 30 minutes and contralateral nephrectomy in wild-type mice (C57BL/6) or caspase-3(-/-) mice.Results Compared with their wild-type counterparts, caspase-3(-/-) mice in the early stage of AKI had high urine cystatin C levels, tubular injury scores, and serum creatinine levels. Electron microscopy revealed evidence of tubular epithelial cell necrosis in caspase-3(-/-) mice, and immunohistochemistry showed upregulation of the necroptosis marker receptor-interacting serine/threonine-protein kinase 3 (RIPK3) in renal cortical sections. Western blot analysis further demonstrated enhanced levels of phosphorylated RIPK3 in the kidneys of caspase-3(-/-) mice. In contrast, caspase-3(-/-) mice had less microvascular congestion and activation in the early and extension phases of AKI. In the long term (3 weeks after IRI), caspase-3(-/-) mice had reduced microvascular rarefaction and renal fibrosis, as well as decreased expression of alpha-smooth muscle actin and reduced collagen deposition within peritubular capillaries. Moreover, caspase-3(-/-) mice exhibited signs of reduced tubular ischemia, including lower tubular expression of hypoxia-inducible factor-1alpha and improved tubular injury scores.Conclusions These results establish the pivotal importance of caspase-3 in regulating microvascular endothelial cell apoptosis and renal fibrosis after IRI. These findings also demonstrate the predominant role of microvascular over tubular injury as a driver of progressive renal damage and fibrosis after IRI. |
