Impaired endothelial proliferation and mesenchymal transition contribute to vascular rarefaction following acute kidney injury

Abstract

Acute kidney injury induces the loss of renal microvessels, but the fate of endothelial cells and the mechanism of potential vascular endothelial growth factor (VEGF)-mediated protection is unknown. Cumulative cell proliferation was analyzed in the kidney of Sprague-Dawley rats following ischemia-reperfusion (I/R) injury by repetitive administration of BrdU (twice daily) and colocalization in endothelial cells with CD31 or cablin. Proliferating endothelial cells were undetectable for up to 2 days following I/R and accounted for only ∼1% of BrdU-positive cells after 7 days. VEGF-121 preserved vascular loss following I/R but did not affect proliferation of endothelial, perivascular cells or tubular cells. Endothelial mesenchymal transition states were identified by localizing endothelial markers (CD31, cablin, or infused tomato lectin) with the fibroblast marker S100A4. Such structures were prominent within 6 h and sustained for at least 7 days following I/R. A Tie-2-cre transgenic crossed with a yellow fluorescent protein (YFP) reporter mouse was used to trace the fate of endothelial cells and demonstrated interstititial expansion of YFP-positive cells colocalizing with S100A4 and smooth muscle actin following I/R. The interstitial expansion of YFP cells was attenuated by VEGF-121. Multiphoton imaging of transgenic mice revealed the alteration of YFP-positive vascular cells associated with blood vessels characterized by limited perfusion in vivo. Taken together, these data indicate that vascular dropout post-AKI results from endothelial phenotypic transition combined with an impaired regenerative capacity, which may contribute to progressive chronic kidney disease.

Antithrombin III prevents progression of chronic kidney disease following experimental ischaemic‐reperfusion injury

“…Progressive tubulointerstitial fibrosis is the hallmark of AKI‐to‐CKD progression. In agreement with previous studies 28, 30, 31, we observed that both NX‐IRI and BI‐IRI led to increased renal fibrosis following AKI. It was noteworthy that BI‐IRI also caused slightly but significantly increased collagen accumulation at 5 weeks after AKI regardless of no significantly increase in Scr compared with sham, indicating that the histological change of kidney tissues might precede the decline of biochemistry parameters.…”

Hematopoietic MicroRNA-126 Protects against Renal Ischemia/Reperfusion Injury by Promoting Vascular Integrity

“…11,12 Because of their limited replicative capacity, renal ECs are thought to be insufficiently capable to completely repair the injured endothelium of the peritubular capillary plexus after IRI. 13,14 Therefore, current therapeutic strategies to prevent microvascular loss have focused on the prevention of pericyte perturbation to reduce capillary rarefaction. [15][16][17][18] However, once rarefaction has occurred, these strategies may fail to induce sufficient revascularization required to reverse renal dysfunction.…”

Strategies to improve the understanding of long-term renal consequences after neonatal acute kidney injury

“…Research over the past decade has provided substantial data showing that AKI leads to CKD (2)(3)(4)(5)(6)(7)(8). Although the exact mechanisms underlying the progression from AKI to CKD continue to be explored, endothelial damage may play a critical role in outcomes, leading to nephron drop-out, interstitial fibrosis, and, ultimately, CKD (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). A full review of the data on the link between AKI and CKD in animals and adults is beyond the scope of this article but has recently been performed (5).…”

“…Acute kidney injury (AKI) has emerged as a risk factor for future CKD in both pediatric (2,3) and adult observational studies (4,5). Animal models have begun to identify the pathophysiologic mechanisms that lead to the development of CKD after episodes of AKI (5)(6)(7)(8). While there has been significant progress in studying the short-term implications of AKI in neonates, numerous critical gaps in our understanding of the epidemiology of neonatal AKI and the future development of CKD remain.…”