A Comprehensive Review of Engineered Bone Marrow Mesenchymal Stem Cell-Derived Exosomes as Nanotheranostic Platforms for Acute and Chronic Kidney Diseases

Sustained Activation of EGFR Triggers Renal Fibrogenesis after Acute Kidney Injury

BackgroundAcute hypoxic proximal tubule (PT) injury and subsequent maladaptive repair present high mortality and increased risk of acute kidney injury (AKI) - chronic kidney disease (CKD) transition. Human bone marrow mesenchymal stem cell-derived exosomes (hBMMSC-Exos) as potential cell therapeutics can be translated into clinics if drawbacks on safety and efficacy are clarified. Here, we determined the real-time effective dose and treatment window of allogeneic hBMMSC-Exos, evaluated their performance on the structural and functional integrity of 3D microfluidic acute hypoxic PT injury platform.MethodshBMMSC-Exos were isolated and characterized. Real-time impedance-based cell proliferation analysis (RTCA) determined the effective dose and treatment window for acute hypoxic PT injury. A 2-lane 3D gravity-driven microfluidic platform was set to mimic PT in vitro. ZO-1, acetylated α-tubulin immunolabelling, and permeability index assessed structural; cell proliferation by WST-1 measured functional integrity of PT.ResultshBMMSC-Exos induced PT proliferation with ED50 of 172,582 µg/ml at the 26th hour. Hypoxia significantly decreased ZO-1, increased permeability index, and decreased cell proliferation rate on 24–48 h in the microfluidic platform. hBMMSC-Exos reinforced polarity by a 1.72-fold increase in ZO-1, restored permeability by 20/45-fold against 20/155 kDa dextran and increased epithelial proliferation 3-fold compared to control.ConclusionsThe real-time potency assay and 3D gravity-driven microfluidic acute hypoxic PT injury platform precisely demonstrated the therapeutic performance window of allogeneic hBMMSC-Exos on ischemic AKI based on structural and functional cellular data. The novel standardized, non-invasive two-step system validates the cell-based personalized theragnostic tool in a real-time physiological microenvironment prior to safe and efficient clinical usage in nephrology.

Nomenclature for kidney function and disease: Executive summary and glossary from a Kidney Disease: Improving Global Outcomes (KDIGO) consensus conference

BackgroundIschemia–reperfusion injury (IRI)-induced acute kidney injury (AKI) can repair itself completely. However, most moderate and severe patients undergoing IRI-AKI progress to chronic kidney disease due to incomplete repair. The present study is aimed to investigate the role of bone marrow mesenchymal stem cell-derived exosomes (MSC-Exo) with indoleamine 2,3-dioxygenase (IDO) overexpression on incomplete repair in mice after IRI.MethodsIRI mice was established by clamping the unilateral renal pedicles and challenged with MSC-Exo. Blood biochemical indexes and inflammation factors contents were measured by ELISA assay. Histopathological examinations were monitored by HE, Masson, Immunohistochemical and TUNEL staining. Immunofluorescence, flow cytometry and immunoblotting were used to detect the polarization of macrophages, respectively.ResultsAs compared to sham operation mice, IRI mice showed high contents of serum BUN and Scr, and more severe damaged kidney tissues on days 1 and 3, which all gradually declined over time, showing the lowest level on day 7 after injury. Once treated with MSCs-Exo that could directly transfer to kidney tubular cells, the restoration of kidney functions significantly accelerated by contrast to IRI mice, and the promotive effects were more obvious in IDO-overexpressed MSCs-Exo (MSCs-Exo-IDO)-treated IRI mice. Furthermore, MSCs-Exo-IDO administration also accelerated renal tubular cells proliferation, restrained tubular cells apoptosis, fibrosis and inflammation factor secretions during self-repair process compared to IRI mice, whose effects were higher than MSCs-Exo-NC-challenged IRI mice and IDO overexpressing plasmid-injected IRI mice. Mechanistically, MSCs-Exo-NC and MSCs-Exo-IDO exposure promoted the polarization from M1 macrophage to M2 macrophage, leading to more anti-inflammatory factors production, and subsequently altered the inflammatory microenvironment of renal tubular cells, which facilitated the self-repair process in mice after IRI.ConclusionMSCs-derived exosome accelerated renal self-repair in IRI mice by activating M2 macrophages polarization, which effects were amplified by IDO overexpression in MSCs. Potentially, genetically modified MSCs-Exo is an effective approach to improve renal self-repair in IRI-AKI mice.

Do Children With Acute Kidney Injury Require Long-term Evaluation for CKD?

Acute kidney injury (AKI) and chronic kidney disease (CKD) are interconnected clinical syndromes, and both manifest kidney injury and a decrease in glomerular filtration rate (GFR). Studies have shown that patients with AKI may still have abnormalities in the renal structure after complete recovery of renal function, thereby increasing the risk of CKD and end-stage renal disease (ESRD). However, some patients with renal dysfunction and structural abnormalities may not reach the current diagnostic criteria of AKI or CKD. Therefore, in 2012, the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines for AKI put forward a new concept, acute kidney diseases and disorders, which includes AKI and other newly-identified kidney diseases that do not meet AKI or CKD diagnostic criteria. This new concept was proposed to help increase the identification and exchange of various acute and chronic kidney diseases, and to increase the medical, scientific, and public health levels of the kidney disease field. This article described the concept and staging of acute kidney disease (AKD), as well as the current epidemiological status of AKD and future research directions, aiming to help clinicians correctly identify and assess various acute and chronic kidney diseases. Key words: Acute kidney diseases (AKD); Acute kidney injury (AKI); Chronic kidney disease (CKD); Definition; Stage; Epidemiology

Therapeutic Applications of Mesenchymal Stem Cells to Repair Kidney Injury

Cancer and the Kidney: The Growth of Onco-nephrology

Background and Aims Macrophages are heterogeneous and play pivotal roles in renal injury and repair, making them prime therapeutic targets for kidney disease. However, their diversity and function in the transition from acute kidney injury (AKI) to chronic kidney disease (CKD) remain poorly understood. Here, we employed single-cell RNA-sequencing (scRNA-seq) to identify key macrophage subpopulations involved in renal repair after AKI. We also explored a chemical approach to reprogram macrophages for AKI recovery. Method A mouse model of renal ischemia-reperfusion AKI (IR-AKI) was established. Renal tissue was collected at different time points post-AKI for scRNA-seq analysis. Macrophages were identified and clustered based on gene expression profiles. Gene enrichment analysis and Cellchat were performed for the identification of pro-repair macrophage. Key transcription factors (TFs) were predicted to understand the gene regulatory network of pro-repair macrophages. To induce a pro-repair macrophage phenotype, small molecule compounds targeting key TFs and repair-associated factors were applied to RAW cells in various combinations. The efficacy of these chemical cocktails was evaluated by repair factors levels and transcriptome sequencing analysis. The repair function of chemically reprogrammed macrophages was validated in vitro using co-culture systems with tubular epithelial cells or vascular endothelial cells. Finally, chemical cocktails were administered to AKI mice to reprogram macrophages into a pro-repair functional phenotype to facilitate renal repair. Results We identified 2241 macrophages through renal scRNA-seq, which clustered into seven distinct subgroups. A pro-repair macrophage subpopulation with unique renal repair functions was defined, characterized by high expression of epithelial repair factors (Hbegf, Gdf15, Spink1) and angiogenic factors (Vegfa, Ccn1, Timp3, Adamts1). Cellchat analysis showed that pro-repair macrophages have strong interactions with damaged tubular epithelial cells and endothelial cells. Gene regulatory network analysis identified Cebpb, Ppara and Egr1 as core transcription factors governing pro-repair macrophage function. Furthermore, we screened fifteen combinations of small molecule drugs and found that the FDRC chemical cocktail effectively activates Cebpb, Ppara and EGR1 in RAW cells, leading to significant expression of Hbegf, Gdf15, and Vegfa. RNA-seq found that FDRC-reprogrammed macrophages display a unique gene expression profile distinct from M0 or M2 macrophages, which significantly increased gene expressions related to angiogenesis, anti-inflammatory, and wound healing. FDRC-reprogrammed RAW cells can significantly promote their proliferation when co-cultured with endothelial cells and tubular epithelial cells. Notably, FDRC successfully reprogrammed macrophages toward a pro-repair-like phenotype in IR-AKI mice, which significantly ameliorated tubular injury and peritubular capillary rarefaction, and potently prevented the AKI-to-CKD transition. Conclusion Our study uncovers a novel pro-repair macrophage subset during AKI and introduces a promising chemical reprogramming cocktail to manipulate macrophage phenotype in vivo, facilitating the repair of renal tubules and peritubular capillaries.

Phosphatase and Tensin Homolog on chromosome Ten (PTEN) has emerged as a key protein that governs the response to kidney injury. Notably, renal adaptive repair is important for preventing acute kidney injury (AKI) to chronic kidney disease (CKD) transition. To test the role of PTEN in renal repair after acute injury, we constructed a mouse model that overexpresses PTEN in renal proximal tubular cells (RPTC) by crossing PTENfl-stop-fl mice with Ggt1-Cre mice. Mass spectrometry-based proteomics was performed after subjecting these mice to ischemia/reperfusion (I/R). We found that PTEN was downregulated in renal tubular cells in mice and cultured HK-2 cells subjected to renal maladaptive repair induced by I/R. Renal expression of PTEN negatively correlated with NGAL and fibrotic markers. RPTC-specific PTEN overexpression relieved I/R-induced maladaptive repair, as indicated by alleviative tubular cell damage, apoptosis, and subsequent renal fibrosis. Mass spectrometry analysis revealed that differentially expressed proteins in RPTC-specific PTEN overexpression mice subjected to I/R were significantly enriched in phagosome, PI3K/Akt, and HIF-1 signaling pathway and found significant upregulation of CHMP2A, an autophagy-related protein. PTEN deficiency downregulated CHMP2A and inhibited phagosome closure and autolysosome formation, which aggravated cell injury and apoptosis after I/R. PTEN overexpression had the opposite effect. Notably, the beneficial effect of PTEN overexpression on autophagy flux and cell damage was abolished when CHMP2A was silenced. Collectively, our study suggests that PTEN relieved renal maladaptive repair in terms of cell damage, apoptosis, and renal fibrosis by upregulating CHMP2A-mediated phagosome closure, suggesting that PTEN/CHMP2A may serve as a novel therapeutic target for the AKI to CKD transition.

Clinical practice guidelines for the provision of renal service in Hong Kong: General Nephrology.

Long-term Outcomes After Acute Kidney Injury: Where We Stand and How We Can Move Forward

Long-Term Outcomes of Acute Kidney Injury

Acute and chronic kidney diseases have devastating consequences on human health. Renal vascular function, glomerular filtration, and epithelial transport are required for water and electrolyte homeostasis. Nephrotoxicity and diseases such as hypertension, diabetes, and metabolic syndrome contribute significantly to acute and chronic kidney diseases (Barnett and Cummings, 2018). These pathological states impact on renal vascular and epithelial function and the ability for the kidney to maintain water and electrolyte homeostasis. Experimental and clinical studies over the past decade determined that there is a transition from acute to chronic kidney injury (Fiorentino et al., 2018). Acute kidney injury in the clinical setting can cause sustained alterations in epithelial transport and renal hemodynamics that increase the risk for developing chronic kidney disease (Sharfuddin and Molitoris, 2011). Currently, there are extremely limited options to treat acute and chronic kidney diseases. A Research Topic on acute and chronic kidney diseases is timely because this is a very fast-moving field that is focused on the tremendous need for kidney disease therapeutics. Articles in this Research Topic advance our understanding of organismal, cellular, and molecular mechanisms that contribute to acute and chronic kidney diseases. The Research Topic has broad interest since it covers acute kidney injury, chronic kidney disease, diabetic nephropathy, and hypertension mediated kidney disease. Research articles span cell signaling, animal studies, human and animal disease pathology studies, renal hemodynamics, glomerular filtration, and renal epithelial transport studies. Thirty contributions focus on novel developments defining renal vascular and epithelial mechanisms that contribute to acute and chronic kidney diseases.

Progression From Acute Kidney Injury to Chronic Kidney Disease: A Pediatric Perspective