Mouse Model Of Kidney Injury Research Articles

Acute kidney disease in mice is associated with early cardiovascular dysfunction

Acute kidney injury (AKI) and chronic kidney disease (CKD) are major health concerns due to their increasing incidence and high mortality. They are interconnected syndromes; AKI without recovery evolves into acute kidney disease (AKD), which can indicate an AKI-to-CKD transition. Both AKI and CKD are associated with a risk of long-term cardiovascular complications, but whether vascular and cardiac dysfunctions can occur as early as the AKD period has not been studied extensively. In a mouse model of kidney injury (KI) with non-recovery, we performed vasoreactivity and echocardiography analyses on days 15 (D15) and 45 (D45) after KI. We determined the concentrations of two major gut-derived protein-bound uremic toxins known to induce cardiovascular toxicity—indoxyl sulfate (IS) and para-cresyl sulfate (PCS)—and the levels of inflammation and contraction markers on D7, D15, and D45. Mice with KI showed acute tubular and interstitial kidney lesions on D7 and D15 and chronic glomerulosclerosis on D45. They showed significant impairment of aorta relaxation and systolic-diastolic heart function, both on D15 and D45. Such dysfunction was associated with downregulation of the expression of two contractile proteins, αSMA and SERCA2a, with a more pronounced effect on D15 than on D45. KI was also followed by a rapid increase in IS and PCS serum concentrations and the expression induction of pro-inflammatory cytokines and endothelial adhesion molecules in serum and cardiovascular tissues. Therefore, these results highlight that AKD leads to early cardiac and vascular dysfunctions. How these dysfunctions could be managed to prevent cardiovascular events deserves further study.

Nanoparticle Transport in Proximal Tubules with Rhabdomyolysis‐induced Necrosis

Renal‐clearable engineered nanoparticles are being explored for their potential to deliver therapeutic agents for kidney disease treatment. A fundamental understanding of how these nanoparticles accumulate in diseased kidneys at the cellular level is essential to enhance their effectiveness and minimize side effects on adjacent healthy tissues. Herein, we report that the accumulation of glutathione‐coated, near‐infrared emitting gold nanoparticles (GS‐AuNPs) correlates strongly with the necrotic stages of injured proximal tubular cells. Using a rhabdomyolysis‐induced acute kidney injury (AKI) mouse model, we observed that GS‐AuNPs were significantly accumulated in the extracellular lumen of proximal tubular epithelial cells (PTECs) at advanced necrotic stage, where cellular debris and released intracellular contents impeded their clearance. In contrast, during early necrosis, GS‐AuNPs were still cleared through the open lumen. Additionally, intracellular uptake of GS‐AuNPs was significantly reduced across all necrotic stages. These findings underscore the need for new strategies to design nanoparticles that can effectively target and be taken up by the diseased tubular cells before extensive necrosis occurs; so that nanoparticle‐mediated drug delivery for kidney disease treatment can be achieved with desired efficacy and precision.

Nanoparticle Transport in Proximal Tubules with Rhabdomyolysis-induced Necrosis.

Renal-clearable engineered nanoparticles are being explored for their potential to deliver therapeutic agents for kidney disease treatment. A fundamental understanding of how these nanoparticles accumulate in diseased kidneys at the cellular level is essential to enhance their effectiveness and minimize side effects on adjacent healthy tissues. Herein, we report that the accumulation of glutathione-coated, near-infrared emitting gold nanoparticles (GS-AuNPs) correlates strongly with the necrotic stages of injured proximal tubular cells. Using a rhabdomyolysis-induced acute kidney injury (AKI) mouse model, we observed that GS-AuNPs were significantly accumulated in the extracellular lumen of proximal tubular epithelial cells (PTECs) at advanced necrotic stage, where cellular debris and released intracellular contents impeded their clearance. In contrast, during early necrosis, GS-AuNPs were still cleared through the open lumen. Additionally, intracellular uptake of GS-AuNPs was significantly reduced across all necrotic stages. These findings underscore the need for new strategies to design nanoparticles that can effectively target and be taken up by the diseased tubular cells before extensive necrosis occurs; so that nanoparticle-mediated drug delivery for kidney disease treatment can be achieved with desired efficacy and precision.

Atypical Protein Kinase C Zeta Is Indispensable for Calcium Oxalate Crystal Clearance in a Dietary-Induced Mouse Model of Kidney Injury

Atypical Protein Kinase C Zeta Is Indispensable for Calcium Oxalate Crystal Clearance in a Dietary-Induced Mouse Model of Kidney Injury

The Nicotinic Acid Receptor HCA2 Regulates Progression of AKI and Development of CKD in Mouse Models of Sepsis and Postischemic Kidney Injury

The Nicotinic Acid Receptor HCA2 Regulates Progression of AKI and Development of CKD in Mouse Models of Sepsis and Postischemic Kidney Injury

An early and stable mouse model of polymyxin-induced acute kidney injury

BackgroundPolymyxins have been revived as a last-line therapeutic option for multi-drug resistant bacteria and continue to account for a significant proportion of global antibiotic usage. However, kidney injury is often a treatment limiting event with kidney failure rates ranging from 5 to 13%. The mechanisms underlying polymyxin-induced nephrotoxicity are currently unclear. Researches of polymyxin-associated acute kidney injury (AKI) models need to be more standardized, which is crucial for obtaining consistent and robust mechanistic results.MethodsIn this study, male C57BL/6 mice received different doses of polymyxin B (PB) and polymyxin E (PE, also known as colistin) by different routes once daily (QD), twice daily (BID), and thrice daily (TID) for 3 days. We continuously monitored the glomerular filtration rate (GFR) and the AKI biomarkers, including serum creatinine (Scr), blood urea nitrogen (BUN), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1). We also performed histopathological examinations to assess the extent of kidney injury.ResultsMice receiving PB (35 mg/kg/day subcutaneously) once daily exhibited a significant decrease in GFR and a notable increase in KIM-1 two hours after the first dose. Changes in GFR and KIM-1 at 24, 48 and 72 h were consistent and demonstrated the occurrence of kidney injury. Histopathological assessments showed a positive correlation between the severity of kidney injury and the changes in GFR and KIM-1 (Spearman’s rho = 0.3167, P = 0.0264). The other groups of mice injected with PB and PE did not show significant changes in GFR and AKI biomarkers compared to the control group.ConclusionThe group receiving PB (35 mg/kg/day subcutaneously) once daily consistently developed AKI at 2 h after the first dose. Establishing an early and stable AKI model facilitates researches into the mechanisms of early-stage kidney injury. In addition, our results indicated that PE had less toxicity than PB and mice receiving the same dose of PB in the QD group exhibited more severe kidney injury than the BID and TID groups.

5-Hydroxytryptamine 1F Receptor Agonist Lasmiditan Differentially Regulates Successful Repair and Failed Repair Genes in a Mouse Model of Acute Kidney Injury.

Increasing evidence substantiates the role of mitochondrial dysfunction, inflammation, fibrosis, and cell senescence in the onset and progression of acute kidney injury (AKI) to chronic kidney disease . The underlying governing cellular and transcriptional events, however, are not fully understood. Recently, the key factors that regulate successful and failed repair states in the proximal tubule have been identified at a single-cell resolution following bilateral ischemia-reperfusion (I/R) in a mouse model of AKI. Previously, our group showed that treatment with the FDA-approved selective 5-hydroxytryptamine receptor 1F agonist lasmiditan following AKI induces mitochondrial biogenesis , restores renal mitochondrial function, and increases renal and vascular recovery in vivo. Here, we assessed the effect of lasmiditan on transcriptional and translational changes that are responsible for successful repair, injury, and failed repair states in the renal cortex following I/R-induced AKI. Increased levels of successful repair genes such as acyl-coA synthase medium-chain family member 2a, low-density lipoprotein receptor-related protein 2, solute carrier family 5 member 12, and hepatocyte nuclear factor 4 alpha were observed with 6 and 12 days of lasmiditan treatment following AKI compared to vehicle control. While 6 days of lasmiditan treatment had no effect on failed repair genes, the administration of lasmiditan for 12 days decreased the levels of vascular cell adhesion protein 1, tumor necrosis factor α, and interleukin-1β, which drive maladaptive repair. These data reveal that lasmiditan treatment post-AKI differentially regulates successful and failed repair gene expression in the renal cortex, likely contributing to the restoration of renal function and providing a potential targeted therapeutic pathway for the treatment of AKI.

Single-cell RNA sequencing data locate ALDH1A2-mediated retinoic acid synthetic pathway to glomerular parietal epithelial cells.

Aldehyde dehydrogenase 1, family member A2, is a retinoic acid-synthesizing enzyme encoded by Aldh1a2 in mice and ALDH1A2 in humans. This enzyme is indispensable for kidney development, but its role in kidney physiology and pathophysiology remains to be fully defined. In this review, we mined single-cell and single-nucleus RNA sequencing databases of mouse and human kidneys and found that glomerular parietal epithelial cells (PECs) express a full set of genes encoding proteins needed for cellular vitamin A uptake, intracellular transport, and metabolism into retinoic acid. In particular, Aldh1a2/ALDH1A2 mRNAs are selectively enriched in mouse and human PECs. Aldh1a2 expression in PECs is greatly increased in a mouse model of anti-glomerular basement membrane glomerulonephritis and moderately induced in a mouse model of ischemia-reperfusion acute kidney injury. Aldh1a2 expression in PECs is substantially repressed in a chronic kidney disease mouse model combining diabetes, hypertension, and partial nephrectomy and is moderately repressed in mouse models of focal segmental glomerulosclerosis and diabetic nephropathy. Single-nucleus RNA sequencing data show that ALDH1A2 mRNA expression in PECs is diminished in patients with chronic kidney disease associated with diabetes, hypertension and polycystic kidney disease. In addition to data mining, we also performed Spearman's rank correlation coefficient analyses and identified gene transcripts correlated with Aldh1a2/ALDH1A2 transcripts in mouse PECs and PEC subtypes, and in human PECs of healthy subjects and patients with AKI or CKD. Furthermore, we conducted Gene Ontology pathway analyses and identified the biological pathways enriched among these Aldh1a2/ALDH1A2-correlated genes. Our data mining and analyses led us to hypothesize that ALDH1A2-mediated retinoic acid synthesis in PECs plays a yet-undefined role in the kidney and that its dysregulation mediates injury. Conditional, PEC-selective Aldh1a2 knockout, RNA silencing and transgenic mouse models will be useful tools to test this hypothesis. Clinical studies on genetics, epigenetics, expression and functions of ALDH1A2 and other genes needed for retinoic acid biosynthesis and signaling are also warranted.

Effects of live and pasteurized forms of Lactobacillus casei Zhang on acute kidney injury and chronic renal fibrosis.

Lactobacillus casei Zhang (Lac.z), isolated from traditional sour horse milk in Inner Mongolia, can alleviate various diseases and promote health. Our previous studies found that pretreatment with live Lac.z (L-Lac.z) could significantly attenuate acute kidney injury and delay the progression of chronic renal fibrosis. However, it is unknown whether these effects could be maintained by pasteurized Lac.z (P-Lac.z). Mouse models of acute kidney injury and chronic renal fibrosis induced by renal bilateral ischemia-reperfusion (BIR) surgery were treated with L-Lac.z or P-Lac.z by gavage. Serum and kidney samples were collected to analyze the extent of renal injury and fibrosis, and proteomics was used to explore the potential mechanisms underlying the differences in the effects of the two forms of Lac.z. The results revealed that treatment with L-Lac.z led to a reduction in serum urea nitrogen levels and in less renal tubular injury and subsequent renal fibrosis after BIR-induced renal injury, whereas these effects were not observed in the P-Lac.z group. Proteomic analysis revealed 19 up-regulated proteins and 39 down-regulated proteins in the P-Lac.z group, and these gene products were associated with growth and stress resistance. The specific nephroprotective effects of L-Lac.z may be independent of the interaction of live probiotics with the host.

Activation of the α7nAChR by GTS-21 mitigates septic tubular cell injury and modulates macrophage infiltration

The most common and serious complication among hospitalized and critically ill patients is sepsis-associated acute kidney damage (S-AKI), which raises the risk of comorbidities and is linked to a high mortality rate. Cholinergic anti-inflammatory pathway (CAP), an anti-inflammatory pathway mediated by the vagus nerve, acetylcholine, and α7 nicotinic acetylcholine receptors (α7nAChRs), offers new perspectives for the treatment of S-AKI. In this study, we investigated the role of CAP and α7nAChR in kidney injury by employing an LPS-induced septic kidney injury mouse model and GTS-21 intervention. C57BL/6 mice were injected with LPS, with or without GTS-21, in different subgroups. Kidney function was assessed by plasma creatinine, histology, and markers of kidney injury 24 h after intervention. The results demonstrated that GTS-21 could inhibit the systemic inflammatory response and directly protect the tubular cell injury from LPS. To explore the novel gene involved in this response, RNA sequencing of the renal proximal tubular epithelial cell (HK-2), pretreated with LPS and GTS-21, was conducted. The results indicate that GTS-21 administration reduces LPS-induced cytokines and chemokines secretion by HK-2, including CCL20, a potent chemokine attracting monocytes/macrophages. Furthermore, a macrophage transmigration assay revealed that GTS-21 inhibits macrophage transmigration by downregulating the expression of CCL20 in HK-2 cells. In conclusion, GTS-21, as an α7nAChR agonist, emerges as a noteworthy and versatile treatment for S-AKI. Its dual function of directly protecting renal tubular cells and regulating inflammatory responses represents a major advancement in the treatment of sepsis-induced AKI. This finding might pave the way for novel approaches to improving patient outcomes and reducing death rates in sepsis-related complications.

Yishen Jiangzhuo decoction attenuates cisplatin‑induced acute kidney injury by inhibiting inflammation, oxidative stress and apoptosis through the TNF signal pathway.

The present study aimed to investigate the therapeutic effects and mechanisms of Yishen Jiangzhuo decoction (YSJZD) in a mouse model of cisplatin-induced acute kidney injury (AKI). The mice were divided into the NC, cisplatin and cisplatin + YSJZD groups. A concentration-dependent effect of YSJZD on cisplatin-induced AKI was observed and the optimal concentration for intervention was calculated. Changes in blood urea nitrogen and serum creatinine levels combined with hematoxylin and eosin and periodic acid-Schiff staining and transmission electron microscopy observations indicated that YSJZD enhanced renal function, reduced pathological injury and protected renal tubular epithelial cells in cisplatin-induced AKI mice. The results of the transcriptomic and enrichment analyses showed that the mechanisms of YSJZD may be associated with inflammation, oxidation, apoptosis and the TNF signal pathway. Immunofluorescence, oxidative stress index, terminal deoxynucleotidyl transferase dUTP nick end labeling assay and western blotting revealed that YSJZD downregulated apoptosis in the renal tissues of AKI mice and further decreased the expression levels of p-p65, p-p38 MAPK, TNF-α, cleaved-caspase-3 and malondialdehyde, while increasing the levels of NAD-dependent protein deacetylase sirtuin-3, glutathione and superoxide dismutase. Overall, the results showed that YSJZD could effectively abrogate cisplatin-induced AKI in mice through mechanisms primarily related to its anti-inflammatory, antioxidative and antiapoptotic effects by inhibited the TNF signal pathway. YSJZD warrants further investigation as a clinical empirical prescription.

Time-restricted feeding protects against cisplatin-induced acute kidney injury in mice.

Time-restricted feeding (TRF), devoid of calorie restriction, is acknowledged for promoting metabolic health and mitigating various chronic metabolic diseases. While TRF exhibits widespread benefits across multiple tissues, there is limited exploration into its impact on kidney function. In this study, our aim was to investigate the potential ameliorative effects of TRF on kidney damage in a mouse model of cisplatin-induced acute kidney injury (AKI). Cisplatin-induced AKI was induced through intraperitoneal injection of cisplatin into C57BL/6 male mice. Mice undergoing TRF were provided unrestricted access to standard chow daily but were confined to an 8-hour feeding window during the dark cycle for 2 weeks before cisplatin injection. The mice were categorized into four groups: control, TRF, cisplatin, and TRF + cisplatin. The tubular damage score and serum creatinine levels were significantly lower in the TRF + cisplatin group compared to the cisplatin group. The TRF + cisplatin group exhibited reduced expression of phosphorylated nuclear factor kappa B, inflammatory cytokines, and F4/80-positive macrophages compared to the cisplatin group. Furthermore, oxidative stress markers for DNA, protein, and lipid were markedly decreased in the TRF + cisplatin group compared to the cisplatin group. TUNEL-positive tubular cells, cleaved caspase-3 expression, and the Bax/Bcl-2 ratio in the TRF + cisplatin group were lower than those in the cisplatin group. TRF, without calorie restriction, effectively mitigated kidney damage by suppressing inflammatory reactions, oxidative stress, and tubular apoptosis in a mouse model of cisplatin-induced AKI. TRF holds promise as a novel dietary intervention for preventing cisplatin-induced AKI.

Not too much, not too little—just the right amount: the story of YAP in the podocyte

Chen etal. identify dysregulation of the transcriptional activator Yes-associated protein in the podocytes of diabetic mouse and human kidneys. Podocyte Yes-associated protein deficiency led to downregulation of the key transcription factor Wilms' tumor 1, and worsened podocyte injury in a mouse model of diabetic kidney injury. Yes-associated protein may therefore play a critical role in diabetic podocyte injury via regulation of Wilms' tumor 1 expression.

Human mesenchymal stromal cells ameliorate cisplatin-induced acute and chronic kidney injury via TSG-6.

Cisplatin is widely used in tumor chemotherapy, but nephrotoxicity is an unavoidable side effect of cisplatin. Several studies have demonstrated that mesenchymal stromal cells (MSCs) ameliorate cisplatin-induced kidney injury, but the underlying mechanisms are unknown. In this study, the cisplatin-induced kidney injury mouse model was established by subjecting a single intraperitoneal injection with cisplatin. One hour before cisplatin injection, the mice received human bone marrow MSCs (hBM-MSCs) with or without siRNA-transfection, recombinant human tumor necrosis factor-α-stimulated gene/protein 6 (rhTSG-6), or PBS through the tail vein. In addition, cisplatin-stimulated HK-2 cells were treated with hBM-MSCs or rhTSG-6. Human BM-MSCs treatment remarkably ameliorated cisplatin-induced acute and chronic kidney injury, as evidenced by significant reductions in serum creatinine (Scr), blood urea nitrogen, tubular injury, collagen deposition, α-smooth muscle actin accumulation, as well as inflammatory responses, and by remarkable increased anti-inflammatory factor expression and Treg cells infiltration in renal tissues. Furthermore, we found that only a few hBM-MSCs engrafted into damaged kidney and that the level of human TSG-6 in the serum of mice increased significantly following hBM-MSCs administration. Moreover, hBM-MSCs significantly increased the viability of damaged HK-2 cells and decreased the levels of inflammatory cytokines in the culture supernatant. However, the knockdown of the TSG-6 gene in hBM-MSCs significantly attenuated their beneficial effects in vivo and in vitro. On the contrary, treated with rhTSG-6 achieved similar beneficial effects of hBM-MSCs. Our results indicate that systemic administration of hBM-MSCs alleviates cisplatin-induced acute and chronic kidney injury in part by paracrine TSG-6 secretion.

Oleanolic Acid Acetate Alleviates Cisplatin-Induced Nephrotoxicity via Inhibition of Apoptosis and Necroptosis In Vitro and In Vivo.

Cisplatin is a widely used anti-cancer drug for treating solid tumors, but it is associated with severe side effects, including nephrotoxicity. Various studies have suggested that the nephrotoxicity of cisplatin could be overcome; nonetheless, an effective adjuvant drug has not yet been established. Oleanolic acid acetate (OAA), a triterpenoid isolated from Vigna angularis, is commonly used to treat inflammatory and allergic diseases. This study aimed to investigate the protective effects of OAA against cisplatin-induced apoptosis and necroptosis using TCMK-1 cells and a mouse model. In cisplatin-treated TCMK-1 cells, OAA treatment significantly reduced Bax and cleaved-caspase3 expression, whereas it increased Bcl-2 expression. Moreover, in a cisplatin-induced kidney injury mouse model, OAA treatment alleviated weight loss in the body and major organs and also relieved cisplatin-induced nephrotoxicity symptoms. RNA sequencing analysis of kidney tissues identified lipocalin-2 as the most upregulated gene by cisplatin. Additionally, necroptosis-related genes such as receptor-interacting protein kinase (RIPK) and mixed lineage kinase domain-like (MLKL) were identified. In an in vitro study, the phosphorylation of RIPKs and MLKL was reduced by OAA pretreatment in both cisplatin-treated cells and cells boosted via co-treatment with z-VAD-FMK. In conclusion, OAA could protect the kidney from cisplatin-induced nephrotoxicity and may serve as an anti-cancer adjuvant.

X-Ray-Based 3D Histopathology of the Kidney Using Cryogenic Contrast-Enhanced MicroCT.

The kidney's microstructure, which comprises a highly convoluted tubular and vascular network, can only be partially revealed using classical 2D histology. Considering that the kidney's microstructure is closely related to its function and is often affected by pathologies, there is a need for powerful and high-resolution 3D imaging techniques to visualize the microstructure. Here, we present how cryogenic contrast-enhanced microCT (cryo-CECT) allowed 3D visualization of glomeruli, tubuli, and vasculature. By comparing different contrast-enhancing staining agents and freezing protocols, we found that the preferred sample preparation protocol was the combination of staining with 1:2 hafnium(IV)-substituted Wells-Dawson polyoxometalate and freezing by submersion in isopentane at -78°C. This optimized protocol showed to be highly sensitive, allowing to detect small pathology-induced microstructural changes in a mouse model of mild trauma-related acute kidney injury after thorax trauma and hemorrhagic shock. In summary, we demonstrated that cryo-CECT is an effective 3D histopathological tool that allows to enhance our understanding of kidney tissue microstructure and their related function.

Bacteria-targeted magnolol-loaded multifunctional nanocomplexes for antibacterial and anti-inflammatory treatment

Natural plant-derived small molecules have shown great potential for their antimicrobial and anti-inflammatory properties. In this study, we successfully developed a nanocomplex consisting of magnolol (Mag), a surfactant with an 18 carbon hydrocarbon chain and multi-amine head groups (C18N3), and a peptide (cyclic 9-amino acid peptide (CARG)) with targeting capabilities for Staphylococcus aureus (S. aureus). The obtained Mag/C18N3/CARG nanocomplexes exhibited strong antibacterial activity against S. aureus. Furthermore, they demonstrated anti-inflammatory effects by reducing the secretion of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β from macrophage inflammatory cells. This was achieved through downregulating the activation of NF-κB, KEAP1, and NRF2 signaling pathways. In a murine skin infection model, the Mag/C18N3/CARG nanocomplexes effectively suppressed the growth of S. aureus in the infected area and promoted wound healing. Additionally, in a mouse model of acute kidney injury (AKI), the nanocomplexes significantly reduced the levels of blood urea nitrogen and creatinine, leading to a decrease in mortality rate. These findings demonstrate the potential of combining natural plant-derived small molecules with C18N3/CARG assemblies as a novel approach for the development of effective and safe antibacterial agents.

Pre-treatment with β-hydroxybutyrate mitigates cisplatin-induced acute kidney injury

β-Hydroxybutyrate (β-HB), the primary circulating ketone body, plays a dual role as both a metabolic fuel and an endogenous signaling molecule, offering diverse systemic benefits. Recent studies have highlighted the renoprotective effects of exogenous β-HB therapy in various animal models of kidney disease. In this investigation, our goal was to assess whether pre-treatment with exogenous β-HB could alleviate kidney damage in a mouse model of cisplatin-induced acute kidney injury (AKI). Prior to cisplatin administration, intraperitoneal administration of β-HB was carried out, and the groups were classified into four: Sham, β-HB, cisplatin, and β-HB + cisplatin. The tubular damage score and serum creatinine levels were significantly lower in the β-HB + cisplatin group compared to the cisplatin group. Furthermore, the expression of phosphorylated NF-κB, inflammatory cytokines, and the quantity of F4/80-positive macrophages in the β-HB + cisplatin group were reduced compared to those in the cisplatin group. Additionally, oxidative stress markers for DNA, protein, and lipid in the β-HB + cisplatin group were markedly diminished compared to those in the cisplatin group. The number of TUNEL-positive and cleaved caspase 3-positive tubular cells in the β-HB + cisplatin group was lower than in the cisplatin group. Pre-treating with exogenous β-HB effectively mitigated kidney damage by suppressing inflammation, oxidative stress, and tubular apoptosis in cisplatin-induced AKI. Therefore, exogenous β-HB as a pre-treatment emerges as a promising and novel strategy for preventing cisplatin-induced AKI.

Precisely Constructing Renal-Clearable and LAP-Activatable Ratiometric Molecular Probes for Early Diagnosis of Acute and Chronic Kidney Injury Via Optimizing Asymmetric DPP Dyes.

Fluorescence analysis is an increasingly important contributor to the early diagnosis of kidney diseases. To achieve precise visualization of the kidneys and early diagnosis of related diseases, an asymmetric pyrrolopyrrolidone (DPP) dye platform with C-aromatic substituents and N-lipophilic/hydrophilic modification was constructed. Based on these, we developed the renal-clearable, water-soluble, and kidney injury biomarker leucine aminopeptidase (LAP) activated ratiometric fluorescent probe DPP-S-L. In the mouse model of cisplatin-induced acute kidney injury and during the development of type 2 diabetes to diabetic kidney disease, we visualized for the first time the upregulation of LAP in the kidney and urine by dual-channel ratiometric fluorescence signal and diagnosed the kidney injury earlier and more sensitively than blood/urine enzyme detection and tissue analysis. This study showcases an excellent asymmetric DPP dye platform and renal-clearable ratiometric fluorescent probe design strategy that is extended to determination and visualization of other biomarkers for early disease diagnosis.

Cyclohexylalanine-Containing α-Helical Amphipathic Peptide Targets Cardiolipin, Rescuing Mitochondrial Dysfunction in Kidney Injury.

Mitochondrial dysfunction is linked to degenerative diseases, resulting from cardiolipin (CL)-induced disruption of cristae structure in the inner mitochondrial membrane (IMM); therefore, preserving cristae and preventing CL remodeling offer effective strategies to maintain mitochondrial function. To identify reactive oxygen species (ROS)-blocking agents against mitochondrial dysfunction, a library of cyclohexylamine-containing cell-penetrating α-helical amphipathic "bundle" peptides were screened. Among these, CMP3013 is selectively bound to abnormal mitochondria, preserving the cristae structure impaired by mitochondria-damaging agents. With a stronger affinity for CL compared with other IMM lipid components, CMP3013 exhibited high selectivity. Consequently, it protected cristae, reduced ROS production, and enhanced adenosine triphosphate (ATP) generation. In mouse models of acute kidney injury, a 1 mg/kg dose of CMP3013 demonstrated remarkable efficacy, highlighting its potential as a therapeutic agent for mitochondrial dysfunction-related disorders. Overall, CMP3013 represents a promising agent for mitigating mitochondrial dysfunction and associated diseases.