Subsequent total joint arthroplasty: Are we learning from the first stage?

BACKGROUND: With the increasing incidence of total joint arthroplasty (TJA), there is a desire to reduce peri-operative complications and resource utilization. As degenerative conditions progress in multiple joints, many patients undergo multiple procedures. AIM: To determine if both physicians and patients learn from the patient's initial arthroplasty, resulting in improved outcomes following the second procedure. METHODS: The institutional database was retrospectively queried for primary total hip arthroplasty (THA) and total knee arthroplasty (TKA). Patients with only unilateral THA or TKA, and patients undergoing same-day bilateral TJA, were excluded. Patient demographics, comorbidities, and implant sizes were collected at the time of each procedure and patients were stratified by first vs second surgery. Outcome metrics evaluated included operative time, length of stay (LOS), disposition, 90-d readmissions and emergency department (ED) visits. RESULTS: A total of 642 patients, including 364 undergoing staged bilateral TKA and 278 undergoing bilateral THA, were analyzed. There was no significant difference in demographics or comorbidities between the first and second procedure, which were separated by a mean of 285 d. For THA and TKA, LOS was significantly less for the second surgery, with 66% of patients having a shorter hospitalization (P < 0.001). THA patients had significantly decreased operative time only when the same sized implant was utilized (P = 0.025). The vast majority (93.3%) of patients were discharged to the same type of location following their second surgery. However, when a change in disposition was present from the first surgery, patients were significantly more likely to be discharged to home after the second procedure (P = 0.033). There was no difference between procedures for post-operative readmissions (P = 0.438) or ED visits (P = 0.915). CONCLUSION: After gaining valuable experience recovering from the initial surgery, a patient's perioperative outcomes are improved for their second TJA. This may be the result of increased confidence and decreased anxiety, and it supports the theory that enhanced patient education pre-operatively may improve outcomes. For the surgical team, the second procedure of a staged THA is more efficient, although this finding did not hold for TKA.

Gene expression profiling of Jack Pine (Pinus banksiana) under copper stress: Identification of genes associated with copper resistance.

Understanding the genetic response of plants to copper stress is a necessary step to improving the utility of plants for environmental remediation and restoration. The objectives of this study were to: 1) characterize the transcriptome of Jack Pine (Pinus banksiana) under copper stress, 2) analyze the gene expression profile shifts of genotypes exposed to copper ion toxicity, and 3) identify genes associated with copper resistance. Pinus banksiana seedlings were treated with 10 mmoles of copper and screened in a growth chamber. There were 6,213 upregulated and 29,038 downregulated genes expressed in the copper resistant genotypes compared to the susceptible genotypes at a high stringency based on the false discovery rate (FDR). Overall, 25,552 transcripts were assigned gene ontology. Among the top upregulated genes, the response to stress, the biosynthetic process, and the response to chemical stimuli terms represented the highest proportion of gene expression for the biological processes. For the molecular function category, the majority of expressed genes were associated with nucleotide binding followed by transporter activity, and kinase activity. The majority of upregulated genes were located in the plasma membrane while half of the total downregulated genes were associated with the extracellular region. Two candidate genes associated with copper resistance were identified including genes encoding for heavy metal-associated isoprenylated plant proteins (AtHIP20 and AtHIP26) and a gene encoding the pleiotropic drug resistance protein 1 (NtPDR1). This study represents the first report of transcriptomic responses of a conifer species to copper ions.

Three Alternaria Species, Including a New Species, Causing Leaf Spot Disease of Loquat (Eriobotrya japonica) in China.

Loquat (Eriobotrya japonica) is an economically important subtropical fruit crop in China. Field surveys conducted in different loquat orchards located in Chongqing, Sichuan and Fujian province between 2017-2020 resulted in a collection of 56 Alternaria-like isolates from trees exhibiting symptoms of loquat leaf spot. Multigene phylogenetic analyses using seven gene regions, namely ITS, gapdh, RPB2, tef1, Alt a 1, endoPG and OPA10-2, showed that all the isolates belonged to the genus Alternaria, and supporting morphological analysis identified them as members of species A. alternata, A. gaisen and A. chongqingensis sp. nov. In vitro- and in vivo- pathogenicity tests showed all the identified species to be pathogenic and able to cause leaf spot disease on loquat. Moreover, comprehensive phylogenetic analyses employing all combinations of the above seven gene sequences revealed the capability of Alt a 1-tef1-endoPG to provide a well-resolved gene tree for Alternaria spp. at the species level. This study adds to the current knowledge on an unknown species (A. chongqingensis sp. nov.) and the first report of A. gaisen in loquat worldwide.

COVID-19 promotes endothelial dysfunction and thrombogenicity: role of proinflammatory cytokines/SGLT2 prooxidant pathway.

BACKGROUND: COVID-19 is associated with an increased risk of cardiovascular complications. Although cytokines have a predominant role in endothelium damage, the precise molecular mechanisms are far from being elucidated. OBJECTIVES: The present study hypothesized that inflammation in patients with COVID-19 contributes to endothelial dysfunction through redox-sensitive SGLT2 overexpression and investigated the protective effect of SGLT2 inhibition by empagliflozin. METHODS: Human plasma samples were collected from patients with acute, subacute, and long COVID-19 (n = 100), patients with non-COVID-19 and cardiovascular risk factors (n = 50), and healthy volunteers (n = 25). Porcine coronary artery endothelial cells (ECs) were incubated with plasma (10%). Protein expression levels were determined using Western blot analyses and immunofluorescence staining, mRNA expression by quantitative reverse transcription-polymerase chain reaction, and the level of oxidative stress by dihydroethidium staining. Platelet adhesion, aggregation, and thrombin generation were determined. RESULTS: Increased plasma levels of interleukin (IL)-1ß, IL-6, tumor necrosis factor-α, monocyte chemoattractant protein-1, and soluble intercellular adhesion molecule-1 were observed in patients with COVID-19. Exposure of ECs to COVID-19 plasma with high cytokines levels induced redox-sensitive upregulation of SGLT2 expression via proinflammatory cytokines IL-1ß, IL-6, and tumor necrosis factor-α which, in turn, fueled endothelial dysfunction, senescence, NF-κB activation, inflammation, platelet adhesion and aggregation, von Willebrand factor secretion, and thrombin generation. The stimulatory effect of COVID-19 plasma was blunted by neutralizing antibodies against proinflammatory cytokines and empagliflozin. CONCLUSION: In patients with COVID-19, proinflammatory cytokines induced a redox-sensitive upregulation of SGLT2 expression in ECs, which in turn promoted endothelial injury, senescence, platelet adhesion, aggregation, and thrombin generation. SGLT2 inhibition with empagliflozin appeared as an attractive strategy to restore vascular homeostasis in COVID-19.

Increasing the use of anxiolysis and analgesia for paediatric procedures in a community emergency department network: a quality improvement initiative.

Prior reports describe the care children receive in community EDs (CEDs) compared with paediatric EDs (PEDs) as uneven. The Emergency Medical Services for Children (EMSC) initiative works to close these gaps using quality improvement (QI) methodology. Project champion from a community hospital network identified the use of safe pharmacological and non-pharmacological anxiolysis and analgesia (A&A) as one such gap and partnered with EMSC to address it. Our primary Specific, Measurable, Achievable, Relevant and Time-Bound (SMART) aim was to increase intranasal midazolam (INM) use for common, anxiety-provoking procedures on children <8 years of age from 2% to 25% in a year.EMSC facilitated a QI team with representation from the CED and regional children's hospitals. Following the model for improvement, we initiated a process analysis of this CED A&A practice. Review of all paediatric procedural data identified common anxiety-provoking simple procedures as laceration repairs, abscess drainage and foreign body removal. Our SMART aims were benchmarked to two regional PEDs and tracked through statistical process control. A balancing metric was ED length of stay (ED LOS) for patients <8 years of age requiring a laceration repair. Additionally, we surveyed CED frontline staff and report perceptions of changes in A&A knowledge, attitudes and practice patterns. These data prioritised and informed our key driver diagram which guided the Plan-Do-Study-Act (PDSA) cycles, including guideline development, staff training and cognitive aids.Anxiety-provoking simple procedures occurred on average 10 times per month in children <8 years of age. Through PDSA cycles, the monthly average INM use increased from 2% to 42%. ED LOS was unchanged, and the perceptions of provider's A&A knowledge, attitudes and practice patterns improved.A CED-initiated QI project increased paediatric A&A use in a CED network. An A&A toolkit outlines our approach and may simplify spread from academic children's hospitals to the community.

A Novel RNA Aptamer as Synthetic Inducer of DasR Controlled Transcription.

Progress in the synthetic biology field is driven by the development of new tools for synthetic circuit engineering. Traditionally, the focus has relied on protein-based designs. In recent years, the use of RNA-based tools has tremendously increased, due to their versatile functionality and applicability. A promising class of molecules is RNA aptamers, small, single-stranded RNA molecules that bind to a target molecule with high affinity and specificity. When targeting bacterial repressors, RNA aptamers allow one to add a new layer to an established protein-based regulation. In the present study, we selected an RNA aptamer binding the bacterial repressor DasR, preventing its binding to its operator sequence and activating DasR-controlled transcription in vivo. This was made possible only by the combination of an in vitro selection and subsequent in vivo screening. Next-generation sequencing of the selection process proved the importance of the in vivo screening for the discovery of aptamers functioning in the cell. Mutational and biochemical studies led to the identification of the minimal necessary binding motif. Taken together, the resulting combination of bacterial repressor and RNA aptamer enlarges the synthetic biology toolbox by adding a new level of regulation.

Adapting to Visual Noise Alleviates Visual Snow.

Purpose: Visual snow syndrome-characterized by flickering specks throughout the visual field and accompanied by other symptoms-can disrupt daily life and affects roughly 2% of the population. However, its neural bases remain mysterious, and treatments are lacking. Here, we report the first intervention that can temporarily eliminate the visual snow symptom, allowing many observers to see the world without snow for the first time since symptom onset. Prolonged viewing of a visual stimulus strongly reduces the responsiveness of the visual pathways to subsequent stimuli, and we tested whether such adaptation could affect visual snow. Methods: Participants with visual snow (total n = 27) viewed high-contrast dynamic noise patterns, resembling television static, and then judged the strength of the symptom. Results: Visual snow was temporarily reduced in strength to the point that it was invisible at longer adaptation durations for most observers. The effect followed typical trends of adaptation for physical stimuli in normally sighted observers: Effect duration increased monotonically with duration of exposure to the adapter and was specific to dynamic noise. Conclusions: These results establish that spontaneous neural activity in the visual system is causally related to the visual snow percept. Because they perceive this activity, people with visual snow may provide a unique window into the generation and suppression of noise in the visual system. Adaptation allows reliable experimental control over visual snow, and so is a strong candidate for diagnostic testing and a promising tool for further understanding its neural origins, which could in turn aid the development of treatments.

Transcriptome Analysis Reveals Changes in Whole Gene Expression, Biological Process, and Molecular Functions Induced by Nickel in Jack Pine (Pinus banksiana).

Understanding the genetic response of plants to nickel stress is a necessary step to improving the utility of plants in environmental remediation and restoration. The main objective of this study was to generate whole genome expression profiles of P. banksiana exposed to nickel ion toxicity compared to reference genotypes. Pinus banksiana seedlings were screened in a growth chamber setting using a high concentration of 1600 mg of nickel per 1 kg of soil. RNA was extracted and sequenced using the Illumina platform, followed by de novo transcriptome assembly. Overall, 25,552 transcripts were assigned gene ontology. The biological processes in water-treated samples were analyzed, and 55% of transcripts were distributed among five categories: DNA metabolic process (19.3%), response to stress (13.3%), response to chemical stimuli (8.7%), signal transduction (7.7%) and response to biotic stimulus (6.0%). For molecular function, the highest percentages of genes were involved in nucleotide binding (27.6%), nuclease activity (27.3%) and kinase activity (10.3%). Sixty-two percent of genes were associated with cellular compartments. Of these genes, 21.7% were found in the plasma membrane, 16.1% in the cytosol, 12.4% with the chloroplast and 11.9% in the extracellular region. Nickel ions induced changes in gene expression, resulting in the emergence of differentially regulated categories. Overall, there were significant changes in gene expression with a total 4128 genes upregulated and 3754 downregulated genes detected in nickel-treated genotypes compared to water-treated control plants. For biological processes, the highest percentage of upregulated genes in plants exposed to nickel were associated with the response to stress (15%), the response to chemicals (11,1%), carbohydrate metabolic processes (7.4%) and catabolic processes (7.4%). The largest proportions of downregulated genes were associated with the biosynthetic process (21%), carbohydrate metabolic process (14.3%), response to biotic stimulus (10.7%) and response to stress (10.7%). For molecular function, genes encoding for enzyme regulatory and hydrolase activities represented the highest proportion (61%) of upregulated gene. The majority of downregulated genes were involved in the biosynthetic processes. Overall, 58% of upregulated genes were located in the extracellular region and the nucleus, while 42% of downregulated genes were localized to the plasma membrane and 33% to the extracellular region. This study represents the first report of a transcriptome from a conifer species treated with nickel.

Left ventricular assist device exchange: a review of indications, operative procedure, and outcomes.

The use of left ventricular assist devices (LVADs) is intended to treat patients with end-stage heart failure. Owing to technological advances, these devices are becoming more durable. However, LVADs may need to be exchanged when complications arise and heart transplantation is not possible. Indications for LVAD exchange (LVADE) include device thrombosis, device infections, and pump component failure. LVADE has historically been associated with a high risk of morbidity and mortality. In this review, we discuss the indications of LVADE, the decisional and technical aspects during surgery, and outcomes.

Isolation of full-length IgG antibodies from combinatorial libraries expressed in the cytoplasm of Escherichia coli.

Here we describe a facile and robust genetic selection for isolating full-length IgG antibodies from combinatorial libraries expressed in the cytoplasm of redox-engineered Escherichia coli cells. The method is based on the transport of a bifunctional substrate comprised of an antigen fused to chloramphenicol acetyltransferase, which allows positive selection of bacterial cells co-expressing cytoplasmic IgGs called cyclonals that specifically capture the chimeric antigen and sequester the antibiotic resistance marker in the cytoplasm. The utility of this approach is first demonstrated by isolating affinity-matured cyclonal variants that specifically bind their cognate antigen, the leucine zipper domain of a yeast transcriptional activator, with subnanomolar affinities, which represent a ~20-fold improvement over the parental IgG. We then use the genetic assay to discover antigen-specific cyclonals from a naïve human antibody repertoire, leading to the identification of lead IgG candidates with affinity and specificity for an influenza hemagglutinin-derived peptide antigen.

A Novel Small NPC1 Promoter Enhances AAV-Mediated Gene Therapy in Mouse Models of Niemann-Pick Type C1 Disease.

Niemann-Pick disease type C1 (NP-C) is a prematurely lethal genetic lysosomal storage disorder with neurological and visceral pathology resulting from mutations in the NPC1 gene encoding the lysosomal transmembrane protein NPC1. There is currently no cure for NP-C, and the only disease modifying treatment, miglustat, slows disease progression but does not significantly attenuate neurological symptoms. AAV-mediated gene therapy is an attractive option for NP-C, but due to the large size of the human NPC1 gene, there may be packaging and truncation issues during vector manufacturing. One option is to reduce the size of DNA regulatory elements that are essential for gene expression, such as the promoter sequence. Here, we describe a novel small truncated endogenous NPC1 promoter that leads to high gene expression both in vitro and in vivo and compare its efficacy to other commonly used promoters. Following neonatal intracerebroventricular (ICV) injection into the CNS, this novel promoter provided optimal therapeutic efficacy compared to all other promoters including increased survival, improved behavioural phenotypes, and attenuated neuropathology in mouse models of NP-C. Taken together, we propose that this novel promoter can be extremely efficient in designing an optimised AAV9 vector for gene therapy for NP-C.

The SGLT2 inhibitor empagliflozin improves cardiac energy status via mitochondrial ATP production in diabetic mice.

Empagliflozin, a sodium-glucose co-transporter 2 inhibitor developed, has been shown to reduce cardiovascular events in patients with type 2 diabetes and established cardiovascular disease. Several studies have suggested that empagliflozin improves the cardiac energy state which is a partial cause of its potency. However, the detailed mechanism remains unclear. To address this issue, we used a mouse model that enabled direct measurement of cytosolic and mitochondrial ATP levels. Empagliflozin treatment significantly increased cytosolic and mitochondrial ATP levels in the hearts of db/db mice. Empagliflozin also enhanced cardiac robustness by maintaining intracellular ATP levels and the recovery capacity in the infarcted area during ischemic-reperfusion. Our findings suggest that empagliflozin enters cardiac mitochondria and directly causes these effects by increasing mitochondrial ATP via inhibition of NHE1 and Nav1.5 or their common downstream sites. These cardioprotective effects may be involved in the beneficial effects on heart failure seen in clinical trials.

The psychosis human connectome project: Design and rationale for studies of visual neurophysiology.

Visual perception is abnormal in psychotic disorders such as schizophrenia. In addition to hallucinations, laboratory tests show differences in fundamental visual processes including contrast sensitivity, center-surround interactions, and perceptual organization. A number of hypotheses have been proposed to explain visual dysfunction in psychotic disorders, including an imbalance between excitation and inhibition. However, the precise neural basis of abnormal visual perception in people with psychotic psychopathology (PwPP) remains unknown. Here, we describe the behavioral and 7 tesla MRI methods we used to interrogate visual neurophysiology in PwPP as part of the Psychosis Human Connectome Project (HCP). In addition to PwPP (n = 66) and healthy controls (n = 43), we also recruited first-degree biological relatives (n = 44) in order to examine the role of genetic liability for psychosis in visual perception. Our visual tasks were designed to assess fundamental visual processes in PwPP, whereas MR spectroscopy enabled us to examine neurochemistry, including excitatory and inhibitory markers. We show that it is feasible to collect high-quality data across multiple psychophysical, functional MRI, and MR spectroscopy experiments with a sizable number of participants at a single research site. These data, in addition to those from our previously described 3 tesla experiments, will be made publicly available in order to facilitate further investigations by other research groups. By combining visual neuroscience techniques and HCP brain imaging methods, our experiments offer new opportunities to investigate the neural basis of abnormal visual perception in PwPP.

Overexpression of ClWRKY48 from Cunninghamia lanceolata improves Arabidopsis phosphate uptake.

MAIN CONCLUSION: Our findings suggested that ClWRKY48 promoted the expression level of Arabidopsis phosphate transporter genes, enhanced phosphate uptake, and delayed the transition from the vegetative stage to the reproductive phase in Arabidopsis. Phosphorus (P) is an essential mineral for plants that influences their growth and development. ClWRKY48, one of the most highly expressed genes in the leaf, was identified by RT-PCR from Chinese fir [Cunninghamia lanceolata (Lamb.) Hook] (C. lanceolata). Furthermore, when treating C. lanceolata with increasing phosphate (Pi) concentration, the expression level of ClWRKY48 rose in leaves, the trends followed the increasing phosphate concentration treatment. ClWRKY48 is a transcription factor in C. lanceolata, according to the results of a yeast one hybridization experiment. Based on subcellular localization studies, ClWRKY48 is a nuclear-localized protein. Under Pi deficiency conditions, the phosphorus concentration of ClWRKY48 overexpressing Arabidopsis increased by 43.2-51.1% compared to the wild-type. Moreover, under Pi limiting conditions, the phosphate transporter genes AtPHT1;1 (Arabidopsis Phosphate transporter 1;1), AtPHT1;4, and AtPHO1 (Arabidopsis PHOSPHATE 1) were expressed 2.1-2.5, 2.2-2.7, and 6.7-7.3-fold greater than the wild-type in ClWRKY48 transgenic Arabidopsis, respectively. Under Pi-sufficient conditions, the phosphorus concentration and phosphate transporter genes of ClWRKY48 overexpression in Arabidopsis are not significantly different from the wild type. These findings indicated that ClWRKY48 increased phosphate absorption in transgenic Arabidopsis. Furthermore, compared to the wild type, the ClWRKY48 transgenic Arabidopsis not only had a delayed flowering time characteristic but also had lower expression of flowering-related genes AtFT (FLOWERING LOCUS T), AtFUL (FRUITFUL), and AtTSF (TWIN SISTER OF FT). Our findings show that ClWRKY48 enhances phosphate absorption and slows the transition from the vegetative to the reproductive stage in ClWRKY48 transgenic Arabidopsis.

Faster bi-stable visual switching in psychosis.

Bi-stable stimuli evoke two distinct perceptual interpretations that alternate and compete for dominance. Bi-stable perception is thought to be driven at least in part by mutual suppression between distinct neural populations that represent each percept. Abnormal visual perception is observed among people with psychotic psychopathology (PwPP), and there is evidence to suggest that these visual deficits may depend on impaired neural suppression in visual cortex. However, it is not yet clear whether bi-stable visual perception is abnormal among PwPP. Here, we examined bi-stable perception in a visual structure-from-motion task using a rotating cylinder illusion in a group of 65 PwPP, 44 first-degree biological relatives, and 43 healthy controls. Data from a 'real switch' task, in which physical depth cues signaled real switches in rotation direction were used to exclude individuals who did not show adequate task performance. In addition, we measured concentrations of neurochemicals, including glutamate, glutamine, and γ-amino butyric acid (GABA), involved in excitatory and inhibitory neurotransmission. These neurochemicals were measured non-invasively in visual cortex using 7 tesla MR spectroscopy. We found that PwPP and their relatives showed faster bi-stable switch rates than healthy controls. Faster switch rates also correlated with significantly higher psychiatric symptom levels across all participants. However, we did not observe any significant relationships across individuals between neurochemical concentrations and SFM switch rates. Our results are consistent with a reduction in suppressive neural processes during structure-from-motion perception in PwPP, and suggest that genetic liability for psychosis is associated with disrupted bi-stable perception.

Weakened untuned gain control is associated with schizophrenia while atypical orientation-tuned suppression depends on visual acuity.

Perceptual distortions are core features of psychosis. Weakened contrast surround suppression has been proposed as a neural mechanism underlying atypical perceptual experiences. Although previous work has measured suppression by asking participants to report the perceived contrast of a low-contrast target surrounded by a high-contrast surround, it is possible to modulate perceived contrast solely by manipulating the orientation of a matched-contrast center and surround. Removing the bottom-up segmentation cue of contrast difference and isolating orientation-dependent suppression may clarify the neural processes responsible for atypical surround suppression in psychosis. We examined surround suppression across a spectrum of psychotic psychopathology including people with schizophrenia (PSZ; N = 31) and people with bipolar disorder (PBD; N = 29), first-degree biological relatives of these patient groups (PBDrel, PSZrel; N = 28, N = 21, respectively), and healthy controls (N = 29). PSZ exhibited reduced surround suppression across orientations; although group differences were minimal at the condition that produced the strongest suppression. PBD and PSZrel exhibited intermediate suppression, whereas PBDrel performed most similarly to controls. Intriguingly, group differences in orientation-dependent surround suppression magnitude were moderated by visual acuity. A simulation in which visual acuity and/or focal attention interact with untuned gain control reproduces the observed pattern of results, including the lack of group differences when orientation of center and surround are the same. Our findings further elucidate perceptual mechanisms of impaired center-surround processing in psychosis and provide insights into the effects of visual acuity on orientation-dependent suppression in PSZ.

Imaging the Hypothalamo-Neurohypophysial System.

The hypothalamo-neurohypophysial system (HNS) is a brain peptidergic neurosecretory apparatus which is composed of arginine vasopressin (AVP) and oxytocin (OXT) magnocellular neurones and their neuronal processes in the posterior pituitary (PP). In response to specific stimuli, AVP and OXT are secreted into the systemic circulation at the neurovascular interface of the PP, where they act as hormones, but they can also behave as neurotransmitters when released at the somatodendritic compartment or by axon collaterals to other brain regions. Because these peptides are crucial for several physiological processes, including fluid homoeostasis and reproduction, it is of great importance to map the HNS connectome in its entirety in order to understand its functions. In recent years, advances in imaging technologies have provided considerable new information about the HNS. These approaches include the use of reporter proteins under the control of specific promoters, viral tracers, brain-clearing methods, genetically encoded indicators, sniffer cells, mass spectrometry imaging, and spatially resolved transcriptomics. In this review, we illustrate how these latest approaches have enhanced our understanding of the structure and function of the HNS and how they might contribute further in the coming years.

The membrane-associated protein 17 (MAP17) is up-regulated in response to empagliflozin on top of RAS blockade in experimental diabetic nephropathy.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have proven to delay diabetic kidney disease (DKD) progression on top of the standard of care with the renin-angiotensin system (RAS) blockade. The molecular mechanisms underlying the synergistic effect of SGLT2i and RAS blockers is poorly understood. We gave a SGLT2i (empagliflozin), an angiotensin-converting enzyme inhibitor (ramipril), or a combination of both drugs for 8 weeks to diabetic (db/db) mice. Vehicle-treated db/db and db/m mice were used as controls. At the end of the experiment, mice were killed, and the kidneys were saved to perform a differential high-throughput proteomic analysis by mass spectrometry using isobaric tandem mass tags (TMT labeling) that allow relative quantification of the identified proteins. The differential proteomic analysis revealed 203 proteins differentially expressed in one or more experimental groups (false discovery rate < 0.05 and Log2 fold change ≥ ±1). Fourteen were differentially expressed in the kidneys from the db/db mice treated with empagliflozin with ramipril. Among them, MAP17 was up-regulated. These findings were subsequently validated by Western blot. The combined therapy of empagliflozin and ramipril up-regulated MAP17 in the kidney of a diabetic mice model. MAP17 is a major scaffolding protein of the proximal tubular cells that places transporters together, namely SGLT2 and NHE3. Our results suggest that SGLT2i on top of RAS blockade may protect the kidney by boosting the inactivation of NHE3 via the up-regulation of key scaffolder proteins such as MAP17.