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Introduction: Renal dysfunction due to ischemia–reperfusion injury (IRI) is a common problem after kidney transplantation. In recent years, studies on animal models have shown that exosomes derived from mesenchymal stem cells (MSC-Exo) play an important role in treating acute kidney injury (AKI) and promoting tissue repair. The microneedle patch provides a noninvasive and targeted delivery system for exosomes. The purpose of this innovative approach is to combine MSC-Exo with microneedle patches.Method: Exosomes were isolated from MSCs, characterized, and placed in the prepared microneedle patch. Then this construct was applied to the IRI mice model. After 7 days, the gene expression of miR-34a and its targets B-cell lymphoma-2 (BCL-2) and BCL-2-associated X (BAX), along with reactive oxygen species (ROS) and lipid peroxidation (LPO) production, was investigated. Additionally, renoprotection was evaluated for measuring blood urea nitrogen (BUN) and creatinine (Cr) and histopathology detection.Results: After using microneedle patches containing exosomes, the reduction of miR-34a and BAX and enhancement of BCL-2 were observed. Moreover, treatment by this construct decreased the production of ROS, LPO, BUN, and Cr and improved tissue damage.Conclusion: The use of a microneedle patch containing exosomes is a noninvasive method that enables the release of exosomes in a slow manner. In comparison to exosome injection alone, microneedle patch-exosome treatment offers a longer and more targeted effect that improves renal IRI dysfunction and reduces tissue damage, potentially facilitating the clinical application of exosomes and improving graft survival.

The pathogenesis of renal ischemia/reperfusion (I/R) injury involves activating several signal transduction cascade systems in endothelial cells. Sphingosine 1-phospate (S1P) maintains endothelial cell integrity and inhibits lymphocyte egress via the specific S1P1 receptor, and may play a role in reducing ischemic renal injury. We examined the protective effects of a newly identified S1P1-selective agonist, SEW2871, on mouse renal I/R injury. Kidneys were harvested 1–4 days after I/R injury for histopathology, immunofluorescence studies, and quantitative real-time reverse transcriptase-polymerase chain reaction analyses to assess the change in gene expression profiles of inflammation-associated cytokines and adhesion molecules. SEW2871 improved renal function with a 40% reduction in plasma creatinine levels (P<0.01) and a significant reduction in tubular necrosis scores (I/R only: 4.3±0.2 vs I/R+SEW2871: 2.5±0.4, P<0.05) 24 h after ischemia. These changes were accompanied by 69% reduction in circulating lymphocytes, and 77 and 66% reduction in infiltrating neutrophils and macrophages in renal outer medulla, respectively (all P<0.01). The mRNA abundance of tumor necrotic factor-α (TNF-α), P-selectin, E-selectin, and intercellular adhesion molecule-1 (ICAM-1) was markedly increased by I/R injury (3.5-, 4.1-, 3.5-, and 4.8-folds, respectively, all P<0.05 vs sham). SEW2871 treatment partially reversed the upregulation of TNF-α, P-selectin, and ICAM-1 (47, 59, 54%, respectively, vs I/R control: 100%, all P<0.05). The reduction in protein expression of TNF-α, P-selectin, and ICAM-1 was further confirmed with immunofluorescence studies. These results suggest that SEW2871 ameliorates renal I/R injury by inhibiting lymphocyte egress and reducing pro-inflammatory molecules. This new class of renoprotective agent shows promise as a novel approach in preventing/treating ischemic acute renal failure.

This study aimed to investigate the clinicopathological characteristics and prognosis of normotensive and hypertensive IgAN patients with ischemic renal injury. A total of 344 cases of IgAN with ischemic renal injury were included in the study, including 99 normotensive IgAN patients (28.8%) and 245 hypertensive IgAN patients (71.2%). In addition, 467 IgAN patients without ischemic renal injury were included as controls, including 205 normotensive patients and 262 hypertensive patients. Clinicopathological and prognostic data were collected and analyzed. Compared with patients without ischemic renal injury, IgAN patients with ischemic renal injury displayed a higher proportion of hypertention, a higher proportion of ischemic glomerulosclerosis, tubular atrophy/interstitial fibrosis and vascular lesions (all p < .05). There was no significant difference in cumulative survival between the normotensive IgAN patients groups (Log-rank χ 2  = 0.479; p = .489). Furthermore, ischemic renal injury was not a risk factor for end-point events in normotensive IgAN patients (HR = 1.103; 95% CI: 0.279-4.365; p = .889). There was lower cumulative survival in hypertensive IgAN patients with ischemic renal injury (Log-rank χ 2  = 11.352, p = .001). Moreover, ischemic renal injury was a risk factor for end-point events in hypertensive IgAN patients (HR = 1.889; 95% CI: 1.124-3.178; p = .016). Ischemic renal injury can occur in normotensive IgAN patients. Although the pathological changes may not affect the long-term prognosis of normotensive IgAN patients, the prognosis for hypertensive IgAN patients remains poor. Therefore, increased attention should be paid to the clinical management of ischemic lesions in hypertensive IgAN patients.

Background Renal ischemic/reperfusion (I/R) injury leads to acute kidney injury with multiple organ damage. Klotho has anti-inflammatory and antioxidant capacities and protects the heart and kidneys against I/R injury. This study aimed to determine whether Klotho is involved in the cardioprotective effect of limb ischemic per-conditioning (LIPerC) during renal I/R injury. Methods Sprague-Dawley rats were randomly divided into three groups: Sham, I/R underwent bilateral occlusions of the renal pedicles for 60 min followed by reperfusion for 24 h, and LIPerc + I/R, which underwent cyclic I/R of the left femoral artery performed during renal ischemia. After 24 h, plasma, urine, and kidney and heart tissue were collected. Renal and cardiac functional biomarkers, soluble Klotho, oxidative stress, and inflammatory mediators were assessed. Results Renal I/R injury caused a decrease in soluble Klotho and increased blood urea nitrogen, creatinine, troponin I, and LDH ( p  < 0.01). Moreover, it established oxidative stress and histopathological changes in the kidney and myocardium. The levels of TNF-α and NF-κB were upregulated, and Klotho ( p  < 0.01) was downregulated in the post-I/R cardiac tissue. LIPerC improved the histopathological changes and suppressed the oxidative status and inflammation. LIPerC could not compensate for the Klotho expression in the heart tissue. However, correlations between plasma levels and heart expression of Klotho with oxidative and inflammatory signals could confirm the role of Klotho in the healing effect of LIPerC on remote cardiac injury. Conclusion LIPerC may potentially ameliorate the remote cardiac dysfunction induced by renal I/R injury by modulating oxidative and inflammatory signals associated with the Klotho protein.

We isolated a clonal cell line (4E) from kidneys of mice expressing green fluorescent protein controlled by the endothelial-specific Tie2 promoter. When grown in a three-dimensional matrigel matrix they formed a fluorescent capillary network. In vivo angiogenesis assays using growth factor-depleted matrigel implanted plugs promoted a moderate angiogenesis of host endothelial cells. Using vascular endothelial growth factor (VEGF)-A and fibroblast growth factor-2 in the plugs containing 4E-cells resulted in a robust vasculogenesis. Transplantation of 4E cells into mice with acute renal ischemia showed selective engraftment in the ischemic kidney which promoted tubular regeneration by increasing epithelial proliferation and inhibiting apoptosis. This resulted in an accelerated functional recovery 3 days after ischemia. These mice showed a 5-fold increase in tissue VEGF expression compared to controls, but no difference in plasma VEGF level corresponding with better preservation of peritubular capillaries, perhaps due to a local paracrine effect following systemic 4E infusion. One month after ischemia, 9% of engrafted 4E cells expressed green fluorescent protein in the peritubular region while half of them expressed α-smooth muscle actin. Our study shows that kidney mesenchymal stem cells are capable of differentiation toward endothelial and smooth muscle cell lineages in vitro and in vivo, support new blood vessel formation in favorable conditions and promote functional recovery of an ischemic kidney.

Background Renal ischemia-reperfusion injury (I/RI) is a major medical problem related to high mortality and morbidity. Klotho plays a critical role in the kidney pathogenesis of I/RI. The current study aimed to investigate the effect of cyclic remote ischemic perconditioning (RIPerC) on renal downregulation of the Klotho protein in bilateral ischemic reperfusion (BIR). Material and method Twenty-four Sprague-Dawley rats were divided into (I) sham group which was subjected to abdominal mid-line incision without ischemia; (II) BIR group which was exposed to 60 min ischemia followed by 24 h of reperfusion; and (III) The BIR + RIPerC group which was subjected to the same renal BIR and occlusion of the left femoral artery (cyclic 4*5’/5’). After 24-h, the blood and kidney samples were collected. Plasma creatinine (Cr) levels and blood urea nitrogen (BUN) were determined. Total antioxidant capacity (TAC); total oxidant status (TOS); oxidative stress index (OSI); mRNA levels of IL-6, TNF-α, NF-kβ, IL-10, and klotho; and pathological changes were evaluated in the renal tissues. Results BIR resulted in renal dysfunction, as confirmed by higher plasma levels of Cr and BUN and structural changes. This was accompanied by increased TOS levels, OSI index, and decreased TAC levels. IL-6, TNF-α and NF-kβ upregulated, and klotho and IL-10 downregulated after renal ischemia. In the BIR + RIPerC group, RIPerC attenuated the destructive effects of BIR. RIPerC was effective in decreasing oxidative stress and inflammation. However, this procedure cannot upregulate the Klotho gene. Conclusion Remote ischemic per-conditioning provides protection against renal ischemic reperfusion injury without the klotho pathway.

T cells are thought to be involved in the pathogenesis of renal ischemia–reperfusion injury (IRI); however, earlier studies have not found significant T-cell numbers in the kidney following injury. In this study we test the hypothesis that T cells transiently infiltrate the kidney following reperfusion and leave behind T-cell-derived cytokines such as interferons and interleukins, thus triggering an inflammatory reaction. An early rise of infiltrating T cells was coupled with a decrease in both circulating lymphocytes and CD4+ cells of periarterial lymphocyte aggregates. The renal expression of several chemokines was rapidly and markedly increased by ischemia–reperfusion (IR). Sphingosine-1-phosphate type 1 receptor agonists have been shown to protect kidneys from injury. One of these agonists given before IR significantly reduced histologically assessed renal injury, circulating lymphocyte numbers, and renal T-cell infiltration. This pretreatment did not, however, affect the increase in T-cell chemokines but caused an increase in CD4+ cells in the renal lymphatic system. We conclude that T-cell infiltration is an early event after IRI and is mediated by several chemokines. Sphingosine-1-phosphate receptor agonists reduce renal injury and T-cell infiltration in spite of chemokine generation by inhibiting T-cell mobilization from both renal and extra-renal lymphoid tissue.

Background/Aims: The aim of this study was to elucidate how high-mobility group box 1 (HMGB1) exacerbates renal ischemic-reperfusion injury (IRI) by inflammatory and immune responses through the toll-like receptor 4 (TLR4) signaling pathway. Methods: A total of 30 wild-type (WT) mice and 30 TLR4 knockout (TLR4-/-) mice were selected and then randomly assigned to the Sham, I/R or HMGB1 groups. The serum and kidney tissues of all mice were collected 24 h after the perfusion. The fully automatic biochemical detector and ELISA were applied to determine the blood urea nitrogen (BUN) and serum creatinine (Scr) levels, and TNF-α, IL-1β, IL-6, IFN-γ and IL-10 levels, respectively. HE staining was used to evaluate kidney tissue damage, immunofluorescence and immunohistochemical staining were performed to observe CD68 and MPO cell infiltration, and flow cytometry was applied to detect immune cells. qRT-PCR and Western blotting were used to detect the expressions of TLR signaling pathway-related genes and proteins, respectively. Results: Compared with the Sham group, the levels of BUN, Scr, TNF-α, IL-1β, IL-6, IFN-γ and IL-10, kidney tissue damage score, CD68 and MPO cell infiltration, the numbers of immune cells, and the expressions of TLR signaling pathway-related genes and proteins in the I/R and HMGB1 groups were significantly up-regulated. In the I/R and HMGB1 groups, the levels of BUN and Scr, TNF-α, IL-1β, IL-6 and IFN-γ, kidney tissue damage score, CD68 and MPO cell infiltration, immune cell numbers, and TLR signaling pathway-related gene and protein expressions in the WT mice were all higher than those in the TLR4-/- mice, but IL-10 level was significantly lower. Similarly, all aforementioned indexes but IL-10 level in the WT and TLR4-/- mice were higher in the HMGB1 group than in the I/R group. Conclusion: Our study indicated that the up-regulation of HMGB1 could exacerbate renal IRI by stimulating inflammatory and immune responses through the TLR4 signaling pathway.c

Acute kidney injury (AKI) has been found to be a serious clinical problem with high morbidity and mortality, and is associated with acute inflammatory response and sympathetic activation that subsequently play an important role in the development of AKI. It is well known that the sympathetic nervous system (SNS) and immune system intensely interact and mutually control each other in order to maintain homeostasis in response to stress or injury. Evidence has shown that the superior cervical sympathetic ganglion (SCG) participates in the bidirectional network between the immune and the SNS, and that the superior cervical ganglionectomy has protective effect on myocardial infarction, however, the role of the SCG in the setting of renal ischemic reperfusion injury has not been studied. Here, we sought to determine whether or not the SCG modulates renal ischemic reperfusion (IR) injury in rats. Our results showed that bilateral superior cervical ganglionectomy (SCGx) 14 days before IR injury markedly reduced the norepinephrine (NE) in plasma, and down-regulated the increased expression of tyrosine hydroxylase (TH) in the kidney and hypothalamus. Sympathetic denervation by SCGx in the AKI group increased the level of blood urea nitrogen (BUN) and kidney injury molecule-1 (KIM-1), and exacerbated renal pathological damage. Sympathetic denervation by SCGx in the AKI group enhanced the expression of pro-inflammatory cytokines in plasma, kidney and hypothalamus, and increased levels of Bax in denervated rats with IR injury. In addition, the levels of purinergic receptors, P2X3R and P2X7R, in the spinal cord were up-regulated in the denervated rats of the IR group. In conclusion, these results demonstrate that the sympathetic denervation by SCGx aggravated IR-induced AKI in rats via enhancing the inflammatory response, thus, the activated purinergic signaling in the spinal cord might be the potential mechanism in the aggravated renal injury.

Background Pulmonary complications following renal ischemia-reperfusion injury (IRI) occur in a gender-dependent manner. Moreover, an imbalance in the renin-angiotensin system (RAS) exacerbates both renal and pulmonary diseases. Overactivation of the classical RAS component the angiotensin type 1 receptor (AT1R) and angiotensin II may worsen renal IRI and remote organ damage, with gender-specific differences. This study aims to investigate the effect of renal IR on lung injury across genders. Methods Sixty Wistar rats (30 females, 30 males) were randomly assigned to three groups within each gender: Sham, IR (Isch), and IR with losartan (AT1R antagonist; Isch). Bilateral renal ischemia was induced for 45 min in all groups except the sham group. After 24 h of reperfusion, blood samples were collected for serum analysis, and kidney and lung tissues were harvested for histopathological examination, as well as assessment of malondialdehyde (MDA), and nitrite levels. The left lung was also weighed to evaluate pulmonary edema. Results Renal IR led to notable increases in plasma creatinine, blood urea nitrogen (BUN), MDA levels, and the extent of damage to the kidney and lung tissues in both genders. In female rats, losartan significantly decreased serum BUN (56.87 ± 13.1 vs. 112.9 ± 8.9 in groups Isch L and Isch), attenuated kidney scores (7.6 ± 1.3 vs. 12.8 ± 1.2 in groups Isch L and Isch), and increased renal (0.18 ± 0.02 vs. 0.10 ± 0.01 in groups Isch L and sham) and pulmonary nitrite concentrations (0.37 ± 0.07 vs. 0.22 ± 0.009 in groups Isch L and sham) following IR. On the other hand, serum MDA levels increased significantly in males treated with losartan (2.6 ± 0.11 vs. 3.9 ± 0.4 in groups sham and Isch L). Furthermore, losartan mitigated IR-induced lung injury in females (6.5 ± 0.6 vs. 8.3 ± 0.3 in groups Isch L and Isch), whereas it had no significant effect in males. Conclusions Our findings suggest that AT1R blockade with losartan confers a gender-dependent protective effect. Specifically, losartan may mitigate IR-induced renal and pulmonary damage in females, potentially through modulation of the nitric oxide pathway and attenuation of oxidative stress.