Clinical Impacts of Allograft Biopsy in Renal Transplant Recipients 10 Years or Longer After Transplantation.

We aimed to investigate the clinical value of allograft biopsy performed long after renal transplantation. We retrospectively evaluated 99 allograft biopsies in recipients with transplantation vintages of 10 years or longer. Mixed-effects model showed that 1-year estimated glomerular filtration rate (eGFR) slopes after biopsy were significantly greater than those before biopsy [-3.13, -4.42 mL/min/1.73 m2/year, p = 0.01]. Renal biopsy changed the treatment strategies in more than half of the patients. Improvement in eGFR slopes was pronounced in 51 patients with treatment modification based on the biopsy results [2.27 (95% confidence interval (CI): 0.66, 3.89) mL/min/1.73 m2/year], whereas no improvement was observed in those without [0.33 (95% CI: -1.05, 1.71) mL/min/1.73 m2/year, Pinteraction = 0.001]. Among the treatment modifications, enhancement of immunosuppression (IS) led to the most remarkable improvement in eGFR slope. Patients with g scores ≥2 were more likely to receive IS enhancement than those with g scores = 0 [odds ratio; 15.0 (95% CI: 1.65, 136)]. Patients with active glomerulitis (g ≥ 1) without chronicity (cg ≤ 1) showed the most significant improvement in eGFR slope. Given the prevalence of active glomerulitis (g ≥ 1, 21%), which is responsive to treatment even long after transplantation, and the observed magnitude of eGFR slope improvement, renal biopsy can indeed improve allograft prognosis.

Involvement of neutrophils and macrophages in exhaustive exercise-induced liver, kidney, heart, and lung injuries.

Moderate exercise is effective for maintaining or improving overall health. However, excessive exercise that exhausts the adaptive reserve of the body or its ability to positively respond to training stimuli can induce tissue damage and dysfunction of multiple organs and systems. Tissue injury, inflammation, and oxidative stress are reportedly induced in the skeletal muscles, liver, and kidneys after exercise. However, the precise mechanisms underlying acute tissue injury after intense exercise have not yet been fully elucidated. Studies using various experimental models of acute tissue injury, other than intense exercise, have demonstrated infiltration of inflammatory cells, including neutrophils and macrophages. These cells infiltrate injured tissues and induce inflammatory and oxidative stress responses by producing inflammatory cytokines and reactive oxygen species, thereby exacerbating tissue injury. In addition to the activation of blood neutrophils and increase in their levels during and/or after prolonged or intense exercise, chemokines that contribute to leukocyte migration are released, facilitating the migration of neutrophils and monocytes into tissues. Therefore, neutrophils and macrophages, activated by exhaustive exercise, may infiltrate tissues and contribute to exhaustive exercise-induced tissue injury. Recently, the contributions of neutrophils and macrophages to various tissue injuries caused by exhaustive exercise have been reported. In this review, we summarize the involvement of neutrophils and monocytes/macrophages in exhaustive exercise-induced non-skeletal muscle tissue injury. In addition, we present novel data demonstrating the contribution of neutrophils and macrophages to exhaustive exercise-induced cardiac and pulmonary injuries. Our study findings and the evidence presented in this review suggest that neutrophils and macrophages may play pivotal roles in exhaustive exercise-induced tissue injuries.

Idebenone protects the kidneys of rats with renovascular arterial hypertension by inhibiting oxidative stress and apoptosis.

Here, the protective effect of antioxidant Idebenone (IDB) on renovascular hypertension was studied. The two-kidney one-clip (2K-1C) model of renal hypertension was established. The rats were divided into 3 groups: sham-operation group, 2K-1C renal hypertensive rats' model group and model treated with IDB group. The mean arterial blood pressure (MBP) of rats was measured and pathological condition of kidney was observed by H&E staining. The change of renal damage biomarkers (Cre, BUN, urine proteins), inflammatory factors (IL-6, IL-1ß and TNF-α), oxidative stress ratio and key factors (MDA, SOD and CAT) were assessed by kits. The apoptosis key proteins (BAD, BAX, Caspase9, GSK-3ß) were detected via Western blot. The 2K-1C model of renal hypertension was established. IDB reduced the MBP, Cre, BUN, urine proteins and improved the pathological condition of 2K-1C kidney. IDB restrained the inflammation factors (IL-6, IL-1ß and TNF-α) and oxidative stress in kidney of renal hypertensive rats' model. Besides, IDB suppressed the expression of apoptosis key factors (BAD, BAX, Caspase9, GSK-3ß) in kidney of renal hypertensive rats' model. IDB protects the kidneys of rats with renovascular arterial hypertension by inhibiting inflammation, oxidative stress, and apoptosis. These findings might provide medication guidance for IDB in renovascular arterial hypertension.

Glucosylceramide synthase modulation ameliorates murine renal pathologies and promotes macrophage effector function in vitro.

While significant advances have been made in understanding renal pathophysiology, less is known about the role of glycosphingolipid (GSL) metabolism in driving organ dysfunction. Here, we used a small molecule inhibitor of glucosylceramide synthase to modulate GSL levels in three mouse models of distinct renal pathologies: Alport syndrome (Col4a3 KO), polycystic kidney disease (Nek8jck), and steroid-resistant nephrotic syndrome (Nphs2 cKO). At the tissue level, we identified a core immune-enriched transcriptional signature that was shared across models and enriched in human polycystic kidney disease. Single nuclei analysis identified robust transcriptional changes across multiple kidney cell types, including epithelial and immune lineages. To further explore the role of GSL modulation in macrophage biology, we performed in vitro studies with homeostatic and inflammatory bone marrow-derived macrophages. Cumulatively, this study provides a comprehensive overview of renal dysfunction and the effect of GSL modulation on kidney-derived cells in the setting of renal dysfunction.

Metastatic Non-Small-Cell Lung Cancer Presenting as Renal Failure From IgA Nephropathy.

Studies have highlighted a potential link between malignancies and immunoglobulin A nephropathy (IgAN). In such studies, the treatment of malignancy improved the symptoms of IgAN. Here, we report a patient case involving a history of hypertension, tobacco use disorder, and chronic kidney disease (CKD) presenting with hematuria with acute renal failure secondary to IgAN per renal biopsy. Prompted by this association, a malignancy workup was performed including computed tomography (CT) body imaging and biopsies of mediastinal and cervical lymph nodes which revealed a metastatic adenocarcinoma. Current knowledge includes a general mechanism behind the development of IgAN that points toward glomerular deposition of tumor-specific immunoglobulin A (IgA) immunoglobulins. However, the association of IgAN and malignancy has no definitive management guidelines. This clinical case serves as an important contribution in the hopes of future development of guidelines regarding the surveillance and management of IgAN in the setting of malignancy.

Effects of long-term dehydration and quick rehydration on the camel kidney: pathological changes and modulation of the expression of solute carrier proteins and aquaporins.

BACKGROUND: Recurrent dehydration causes chronic kidney disease in humans and animal models. The dromedary camel kidney has remarkable capacity to preserve water and solute during long-term dehydration. In this study, we investigated the effects of dehydration and subsequent rehydration in the camel's kidney histology/ultrastructure and changes in aquaporin/solute carrier proteins along with gene expression. RESULTS: In light microscopy, dehydration induced few degenerative and necrotic changes in cells of the cortical tubules with unapparent or little effect on medullary cells. The ultrastructural changes encountered in the cortex were infrequent during dehydration and included nuclear chromatin condensation, cytoplasmic vacuolization, mitochondrial swelling, endoplasmic reticulum/ lysosomal degeneration and sometimes cell death. Some mRNA gene expressions involved in cell stability were upregulated by dehydration. Lesions in endothelial capillaries, glomerular membranes and podocyte tertiary processes in dehydrated camels indicated disruption of glomerular filtration barrier which were mostly corrected by rehydration. The changes in proximal tubules brush borders after dehydration, were accompanied by down regulation of ATP1A1 mRNA involved in Na + /K + pump that were corrected by rehydration. The increased serum Na, osmolality and vasopressin were paralleled by modulation in expression level for corresponding SLC genes with net Na retention in cortex which were corrected by rehydration. Medullary collecting ducts and interstitial connective tissue were mostly unaffected during dehydration. CKD, a chronic nephropathy induced by recurrent dehydration in human and animal models and characterized by interstitial fibrosis and glomerular sclerosis, were not observed in the dehydrated/rehydrated camel kidneys. The initiating factors, endogenous fructose, AVP/AVPR2 and uric acid levels were not much affected. TGF-ß1 protein and TGF-ß1gene expression showed no changes by dehydration in cortex/medulla to mediate fibrosis. KCNN4 gene expression level was hardly detected in the dehydrated camel's kidney; to encode for Ca + + -gated KCa3.1 channel for Ca + + influx to instigate TGF-ß1. Modulation of AQP 1, 2, 3, 4, 9 and SLC protein and/or mRNAs expression levels during dehydration/rehydration was reported. CONCLUSIONS: Long-term dehydration induces reversible or irreversible ultrastructural changes in kidney cortex with minor effects in medulla. Modulation of AQP channels, SLC and their mRNAs expression levels during dehydration/rehydration have a role in water conservation. Cortex and medulla respond differently to dehydration/rehydration.

Urine-derived podocytes from steroid resistant nephrotic syndrome patients as a model for renal-progenitor derived extracellular vesicles effect and drug screening.

BACKGROUND: Personalized disease models are crucial for evaluating how diseased cells respond to treatments, especially in case of innovative biological therapeutics. Extracellular vesicles (EVs), nanosized vesicles released by cells for intercellular communication, have gained therapeutic interest due to their ability to reprogram target cells. We here utilized urinary podocytes obtained from children affected by steroid-resistant nephrotic syndrome with characterized genetic mutations as a model to test the therapeutic potential of EVs derived from kidney progenitor cells (nKPCs). METHODS: EVs were isolated from nKPCs derived from the urine of a preterm neonate. Three lines of urinary podocytes obtained from nephrotic patients' urine and a line of Alport syndrome patient podocytes were characterized and used to assess albumin permeability in response to nKPC-EVs or various drugs. RNA sequencing was conducted to identify commonly modulated pathways after nKPC-EV treatment. siRNA transfection was used to demonstrate the involvement of SUMO1 and SENP2 in the modulation of permeability. RESULTS: Treatment with the nKPC-EVs significantly reduced permeability across all the steroid-resistant patients-derived and Alport syndrome-derived podocytes. At variance, podocytes appeared unresponsive to standard pharmacological treatments, with the exception of one line, in alignment with the patient's clinical response at 48 months. By RNA sequencing, only two genes were commonly upregulated in nKPC-EV-treated genetically altered podocytes: small ubiquitin-related modifier 1 (SUMO1) and Sentrin-specific protease 2 (SENP2). SUMO1 and SENP2 downregulation increased podocyte permeability confirming the role of the SUMOylation pathway. CONCLUSIONS: nKPCs emerge as a promising non-invasive source of EVs with potential therapeutic effects on podocytes with genetic dysfunction, through modulation of SUMOylation, an important pathway for the stability of podocyte slit diaphragm proteins. Our findings also suggest the feasibility of developing a non-invasive in vitro model for screening regenerative compounds on patient-derived podocytes.

Bisphenol P induces increased oxidative stress in renal tissues of C57BL/6 mice and human renal cortical proximal tubular epithelial cells, resulting in kidney injury.

Bisphenol P (BPP) has been detected in human biological samples; however studies on its nephrotoxicity are scarce. Given the susceptibility of kidneys to endocrine-disrupting chemicals, there is an urgent need to investigate the renal toxicity of BPP. This study aimed to evaluate the effects of different concentrations of BPPs on the kidneys of C57BL/6 mice and elucidate the underlying mechanisms of renal damage using a combination of mouse renal transcriptomic data and human renal proximal tubular epithelial cells (HK-2). Mice were exposed to BPP (0, 0.3, 30, 3000 µg/kg bw/d) via gavage for 5 weeks. Renal injury was assessed based on changes in body and kidney weights, serum renal function indices, and histopathological examination. Transcriptomic analysis identified differentially expressed genes and pathways, whereas cellular assays were used to measure cell viability, reactive oxygen species (ROS), apoptosis, and the expression of key genes and proteins. The results show that BPP exposure induces renal injury, as evidenced by increased body weight, abnormal renal function indices, and renal tissue damage. Transcriptomic analysis revealed alterations in genes and pathways related to oxidative stress, p53 signaling, autophagy, and apoptosis. Cellular experiments confirmed that BPP induces oxidative stress and apoptosis. Furthermore, BPP exposure significantly inhibits autophagy, potentially exacerbating apoptosis and contributing to kidney injury. Treatment with a ROS inhibitor (N-Acetylcysteine, NAC) mitigated BPP-induced autophagy inhibition and apoptosis, implicating oxidative stress as a key factor. BPP exposure may lead to renal injury through excessive ROS accumulation, oxidative stress, inflammatory responses, autophagy inhibition, and increased apoptosis. The effects of NAC highlight the role of oxidative stress in BPP-induced nephrotoxicity. These findings enhance our understanding of BPP-induced nephrotoxicity and underscore the need to control BPP exposure to prevent renal disease. This study emphasized the importance of evaluating the safety of new Bisphenol A analogs, including BPP, in environmental toxicology.

Acidic preconditioning induced intracellular acid adaptation to protect renal injury via dynamic phosphorylation of focal adhesion kinase-dependent activation of sodium hydrogen exchanger 1.

BACKGROUND: Disruptions in intracellular pH (pHi) homeostasis, causing deviations from the physiological range, can damage renal epithelial cells. However, the existence of an adaptive mechanism to restore pHi to normalcy remains unclear. Early research identified H+ as a critical mediator of ischemic preconditioning (IPC), leading to the concept of acidic preconditioning (AP). This concept proposes that short-term, repetitive acidic stimulation can enhance a cell's capacity to withstand subsequent adverse stress. While AP has demonstrated protective effects in various ischemia-reperfusion (I/R) injury models, its application in kidney injury remains largely unexplored. METHODS: An AP model was established in human kidney (HK2) cells by treating them with an acidic medium for 12 h, followed by a recovery period with a normal medium for 6 h. To induce hypoxia/reoxygenation (H/R) injury, HK2 cells were subjected to hypoxia for 24 h and reoxygenation for 1 h. In vivo, a mouse model of IPC was established by clamping the bilateral renal pedicles for 15 min, followed by reperfusion for 4 days. Conversely, the I/R model involved clamping the bilateral renal pedicles for 35 min and reperfusion for 24 h. Western blotting was employed to evaluate the expression levels of cleaved caspase 3, cleaved caspase 9, NHE1, KIM1, FAK, and NOX4. A pH-sensitive fluorescent probe was used to measure pHi, while a Hemin/CNF microelectrode monitored kidney tissue pH. Immunofluorescence staining was performed to visualize the localization of NHE1, NOX4, and FAK, along with the actin cytoskeleton structure in HK2 cells. Cell adhesion and scratch assays were conducted to assess cell motility. RESULTS: Our findings demonstrated that AP could effectively mitigate H/R injury in HK2 cells. This protective effect and the maintenance of pHi homeostasis by AP involved the upregulation of Na+/H+ exchanger 1 (NHE1) expression and activity. The activity of NHE1 was regulated by dynamic changes in pHi-dependent phosphorylation of Focal Adhesion Kinase (FAK) at Y397. This process was associated with NOX4-mediated reactive oxygen species (ROS) production. Furthermore, AP induced the co-localization of FAK, NOX4, and NHE1 in focal adhesions, promoting cytoskeletal remodeling and enhancing cell adhesion and migration capabilities. CONCLUSIONS: This study provides compelling evidence that AP maintains pHi homeostasis and promotes cytoskeletal remodeling through FAK/NOX4/NHE1 signaling. This signaling pathway ultimately contributes to alleviated H/R injury in HK2 cells.

The role of protein prenylation inhibition through targeting FPPS by zoledronic acid in the prevention of renal fibrosis in rats.

Renal fibrosis (RF) represents the most widespread pathological condition in chronic kidney disease (CKD). Recently, protein prenylation has been implicated in the fibrosis's progression. The research examined the renoprotective effect of zoledronic acid (ZA) (50 µg/kg/week) in a rat model of carbon tetrachloride (CCl4)-induced RF through targeting protein prenylation. Forty Wistar male rats were split up into the control group, vehicle-treated group, model-RF group, and RF-ZA group. Mean arterial blood pressure (MBP), BUN, serum creatinine, and urine albumin-creatinine ratio (uACR), protein levels of farnesyl pyrophosphate (FPP), tumour necrosis factor-alpha (TNF-α), transforming growth factor-ß (TGF-ß), and malondialdehyde (MDA), and catalase and gene expression of farnesyl pyrophosphate synthase (FPPS) and nuclear factor-kB (NF-κB) were measured. Immunohistochemical staining for renal interleukin-6 (IL-6), α-smooth muscle actin (α-SMA), and caspase-3, as well as histopathological alterations, were assessed. ZA considerably ceased the reduction in MBP, markedly reduced uACR, serum creatinine, BUN, and expression of FPPS, FPP, NF-κB, TGF-ß, TNF-α, and MDA, and significantly increased catalase levels compared to the model-RF rats. ZA ameliorated the CCl4-induced histopathological alterations and suppressed the expression of caspase-3, α-SMA, and IL-6. In conclusion, ZA preserved renal function and prevented renal fibrosis in a rat model. These were achieved through targeting protein prenylation mainly by inhibiting FPPS.

The effect of Polygonum hyrcanicum Rech. f. hydroalcoholic extract on oxidative stress and nephropathy in alloxan-induced diabetic mice.

Diabetic nephropathy, characterized by inflammation and oxidative stress, poses a management challenge. This study investigates the effect of Polygonum hyrcanicum extract on diabetic nephropathy in alloxan-induced diabetic mice. In this experimental animal study, the P. hyrcanicum extract was prepared using continuous macerations. Thirty male Albino mice, divided into five groups, were induced with alloxan-induced diabetes. They received intraperitoneal injections of the plant extract (100 and 200 mg/kg) and metformin (300 mg/kg) for four weeks. Kidney and blood samples were collected to assess protein carbonyl, glutathione, lipid peroxidation, TNF-α and IL-6 levels. The amount of total flavonoid and phenolic content in the hydroalcoholic extract of P. hyrcanicum were 7.5 ± 0.3 mg of quercetin and 88.2 ± 1.3 mg gallic acid per gram of extract respectively. The antioxidant activity level of the hydroalcoholic extract was determined to be 1.78 ± 0.51 mM equivalent per gram of extract. Alloxan administration resulted in a significant reduction in glutathione levels and a significant increase in protein carbonyl, lipid peroxidation, TNF-α, and IL-6 levels. Hydroalcoholic extract of P. hyrcanicum effectively reduced oxidative stress markers and inflammatory cytokines (TNF-α, IL-6), indicating its potential in mitigating diabetic nephropathy. However, no significant difference in efficacy was observed between the 100 mg/kg and 200 mg/kg doses in terms of reducing these toxicities.

Nephron-Specific Lin28A Overexpression Triggers Severe Inflammatory Response and Kidney Damage.

The RNA-binding proteins LIN28A and LIN28B contribute to a variety of developmental biological processes. Dysregulation of Lin28A and Lin28B expression is associated with numerous types of tumors. This study demonstrates that Lin28A overexpression in the mouse nephrons leads to severe inflammation and kidney damage rather than to tumorigenesis. Notably, Lin28A overexpression causes inflammation only when expressed in nephrons, but not in the stromal cells of the kidneys, highlighting its cell context-dependent nature. The nephron-specific Lin28A-induced inflammatory response differs from previously described Lin28B-mediated inflammatory feedback loops as it is IL-6 independent. Instead, it is associated with the rapid upregulation of cytokines like Cxcl1 and Ccl2. These findings suggest that the pathophysiological effects of Lin28A overexpression extend beyond cell transformation. Our transgenic mouse model offers a valuable tool for advancing our understanding of the pathophysiology of acute kidney injury, where inflammation is a key factor.

ISG15 accelerates acute kidney injury and the subsequent AKI-to-CKD transition by promoting TGFßR1 ISGylation.

Rationale: Acute kidney injury (AKI) has substantial rates of mortality and morbidity, coupled with an absence of efficacious treatment options. AKI commonly transits into chronic kidney disease (CKD) and ultimately culminates in end-stage renal failure. The interferon-stimulated gene 15 (ISG15) level was upregulated in the kidneys of mice injured by ischemia-reperfusion injury (IRI), cisplatin, or unilateral ureteral obstruction (UUO), however, its role in AKI development and subsequent AKI-to-CKD transition remains unknown. Methods: Isg15 knockout (Isg15 KO) mice challenged with bilateral or unilateral IRI, cisplatin, or UUO were used to investigate its role in AKI. We established cellular models with overexpression or knockout of ISG15 and subjected them to hypoxia-reoxygenation, cisplatin, or transforming growth factor- ß1 (TGF-ß1) stimulation. Renal RNA-seq data obtained from AKI models sourced from public databases and our studies, were utilized to examine the expression profiles of ISG15 and its associated genes. Additionally, published single cell RNA-seq data from human kidney allograft biopsies and mouse IRI model were analyzed to investigate the expression patterns of ISG15 and the type I TGF-ß receptor (TGFßR1). Western blotting, qPCR, co-immunoprecipitation, and immunohistochemical staining assays were performed to validate our findings. Results: Alleviated pathological injury and renal function were observed in Isg15 KO mice with IRI-, cisplatin-, or UUO-induced AKI and the following AKI-to-CKD transition. In hypoxia-reoxygenation, cisplatin or TGF-ß1 treated HK-2 cells, knockout ISG15 reduced stimulus-induced cell fibrosis, while overexpression of ISG15 with modification capacity exacerbated cell fibrosis. Immunoprecipitation assays demonstrated that ISG15 promoted ISGylation of TGFßR1, and inhibited its ubiquitination. Moreover, knockout of TGFßR1 blocked ISG15's fibrosis-exacerbating effect in HK-2 cells, while overexpression of TGFßR1 abolished the renal protective effect of ISG15 knockout during IRI-induced kidney injury. Conclusions: ISG15 plays an important role in the development of AKI and subsequent AKI-to-CKD transition by promoting TGFßR1 ISGylation.

Laparoscopic removal of retroperitoneal schwannoma in renal hilum: a case report.

BACKGROUND: Schwannomas in the renal hilum are rare among retroperitoneal tumors. However, the possibility of malignant findings cannot be ruled out, and surgery is often indicated. This case was expected to be difficult to remove laparoscopically because the tumor was sandwiched between the arteriovenous veins of the renal portal. Sometimes, the tumor should be resected with a conservative approach to the kidney to preserve the renal function. CASE PRESENTATION: Our patient was a 51-year-old Asian-Japanese man who was referred to our department for a retroperitoneal tumor in the renal hilum. Since malignancy could not be ruled out due to its size (45 × 48 × 55 mm) on imaging, the tumor was excised laparoscopically. Histopathology revealed schwannoma. CONCLUSIONS: We herein report a case in which a renal hilar tumor between renal arteriovenous vessels was successfully resected laparoscopically.

Attenuation of renal fibrosis in mice due to lack of bombesin receptor-activated protein homologue.

Bombesin receptor-activated protein (BRAP), encoded by the C6orf89 gene in humans, is expressed in various cells with undefined functions. BC004004, the mouse homologue of C6orf89, has been shown to play a role in bleomycin-induced pulmonary fibrosis through the use of a BC004004 gene knockout mouse (BC004004-/-). In this study, we investigated the potential involvement of BRAP in renal fibrosis using two mouse models: unilateral ureteral obstruction (UUO) and type 2 diabetes mellitus induced by combination of a high-fat diet (HFD) and streptozocin (STZ). BRAP or its homologue was expressed in tubular epithelial cells (TECs) in the kidneys of patients with chronic kidney disease (CKD) and in BC004004+/+ mice. Compared to control mice, BC004004-/- mice exhibited attenuated renal injury and renal fibrosis after UUO or after HFD/STZ treatment. Immunohistochemistry and immunoblot analyses of the kidneys of BC004004+/+ mice after UUO surgery showed a more significant decrease in E-cadherin expression and a more significant increase in both α smooth muscle actin (α-SMA) and vimentin expression compared to BC004004-/- mice. Additionally, stimulation with transforming growth factor-ß1 (TGF-ß1) led to a more significant decrease in E-cadherin expression and a more significant increase in α-SMA and vimentin expression in isolated TECs from BC004004+/+ than in those from BC004004-/- mice. These results suggest that an enhanced epithelial-mesenchymal transition (EMT) process occurred in TECs in BC004004+/+ mice during renal injury, which might contribute to renal fibrosis. The loss of the BRAP homologue in BC004004-/- mice suppressed EMT activation in kidneys and contributed to the suppression of fibrosis during renal injury.

To target cellular senescence in diabetic kidney disease: the known and the unknown.

Cellular senescence represents a condition of irreversible cell cycle arrest, characterized by heightened senescence-associated beta-galactosidase (SA-ß-Gal) activity, senescence-associated secretory phenotype (SASP), and activation of the DNA damage response (DDR). Diabetic kidney disease (DKD) is a significant contributor to end-stage renal disease (ESRD) globally, with ongoing unmet needs in terms of current treatments. The role of senescence in the pathogenesis of DKD has attracted substantial attention with evidence of premature senescence in this condition. The process of cellular senescence in DKD appears to be associated with mitochondrial redox pathways, autophagy, and endoplasmic reticulum (ER) stress. Increasing accumulation of senescent cells in the diabetic kidney not only leads to an impaired capacity for repair of renal injury, but also the secretion of pro-inflammatory and profibrotic cytokines and growth factors causing inflammation and fibrosis. Current treatments for diabetes exhibit varying degrees of renoprotection, potentially via mitigation of senescence in the diabetic kidney. Targeting senescent cell clearance through pharmaceutical interventions could emerge as a promising strategy for preventing and treating DKD. In this paper, we review the current understanding of senescence in DKD and summarize the possible therapeutic interventions relevant to senescence in this field.

See the power in kidney cells with ATP biosensor.

Yamamoto et al. developed an exciting technical advance to examine intracellular adenosine triphosphate levels with single-cell resolution in intact living kidney tissue, including in tubular and vascular segments that lie deep under the kidney surface. The work is a significant advance on prior in vivo biosensor studies, and it allows for mechanistic investigation of alterations in cell metabolism, kidney disease pathobiology, and the effects of drug treatments on energy sources in different kidney cell types.