Mobilized Human Hematopoietic Stem/Progenitor Cells Promote Kidney Repair After Ischemia/Reperfusion Injury

Abstract

Background-Understanding the mechanisms of repair and regeneration of the kidney after injury is of great interest because there are currently no therapies that promote repair, and kidneys frequently do not repair adequately. We studied the capacity of human CD34 ϩ hematopoietic stem/progenitor cells (HSPCs) to promote kidney repair and regeneration using an established ischemia/reperfusion injury model in mice, with particular focus on the microvasculature. Methods and Results-Human HSPCs administered systemically 24 hours after kidney injury were selectively recruited to injured kidneys of immunodeficient mice (Jackson Labs, Bar Harbor, Me) and localized prominently in and around vasculature. This recruitment was associated with enhanced repair of the kidney microvasculature, tubule epithelial cells, enhanced functional recovery, and increased survival. HSPCs recruited to kidney expressed markers consistent with circulating endothelial progenitors and synthesized high levels of proangiogenic cytokines, which promoted proliferation of both endothelial and epithelial cells. Although purified HSPCs acquired endothelial progenitor markers once recruited to the kidney, engraftment of human endothelial cells in the mouse capillary walls was an extremely rare event, indicating that human stem cell mediated renal repair is by paracrine mechanisms rather than replacement of vasculature. Conclusions-These studies advance human HSPCs as a promising therapeutic strategy for promoting renal repair after injury. (Circulation. 2010;121:2211-2220.)

Sitagliptin protects rat kidneys from acute ischemia-reperfusion injury via upregulation of GLP-1 and GLP-1 receptors

“…In the present study, we found that compared with the sham control, the protein expression of apoptotic biomarkers (ie, mitochondrial Bax, cleaved caspase 3 and PARP) were markedly enhanced in the acute IR kidney. Our findings, therefore, corroborated the findings from previ- [19][20][21][22][23]28] . The protein expression of these apoptotic parameters was down-regulated after administration of a low dose of sitagliptin and they were further down-regulated after higher dose of sitagliptin treatment.…”

“…Mitochondrial damage [20][21][22] and cellular apoptosis [19,21,28] have also been reported to be frequent findings after IR injuries in solid organs. In the present study, we found that compared with the sham control, the protein expression of apoptotic biomarkers (ie, mitochondrial Bax, cleaved caspase 3 and PARP) were markedly enhanced in the acute IR kidney.…”

“…Surprisingly, although the epidemiology, etiologies, mechanisms, classification, and prognostic outcomes of acute IR kidney injury have been widely investigated for several decades [16][17][18] , there are still no effective therapeutic strategies for this condition other than supportive treatment. Accordingly, the development of new treatment modalities for acute IR kidney injury is needed [19] .…”

“…Many previous studies have reported that the mechanisms underlying IR injuries in solid organs are multifaceted and involve the generation of reactive oxygen species (ROS) [20][21][22] , oxidative stress [20][21][22] , mitochondrial damage [20][21][22] , apoptosis [19,22] , and a cascade of inflammatory processes [22,23] .…”

EphrinB2 Reverse Signaling Protects against Capillary Rarefaction and Fibrosis after Kidney Injury

“…PTC density was analyzed as described with some modifications. 32 In brief, images (3200) were captured from CD31-stained sections (20 images per mouse). Each image was divided into 266 squares by a grid.…”