How Long Does Deep Brain Stimulation Give Patients Benefit?

INTRODUCTION: One of the most common questions patients ask when they are contemplating deep brain stimulation (DBS) is how long it will last. To guide physicians in answering this query, we performed a scoping review to assess the current state of the literature and to identify the gaps that need to be addressed. MATERIALS AND METHODS: The authors performed a MEDLINE search inclusive of articles from January 1987 (advent of DBS literature) to June 2023 including human and modeling studies written in English. For longevity of therapy data, only studies with a mean follow-up of ≥three years were included. Using the Rayyan platform, two reviewers (JP and RM) performed a title screen. Of the 734 articles, 205 were selected by title screen and 109 from abstract review. Ultimately, a total of 122 articles were reviewed. The research questions we explored were 1) how long can the different components of the DBS system maintain functionality? and 2) how long can DBS remain efficacious in treating Parkinson's disease (PD), essential tremor (ET), dystonia, and other disorders? RESULTS: We showed that patients with PD, ET, and dystonia maintain a considerable long-term benefit in motor scores seven to ten years after implant, although the percentage improvement decreases over time. Stimulation off scores in PD and ET show worsening, consistent with disease progression. Battery life varies by the disease treated and the programming settings used. There remains a paucity of literature after ten years, and the impact of new device technology has not been classified to date. CONCLUSION: We reviewed existing data on DBS longevity. Overall, outcomes data after ten years of therapy are substantially limited in the current literature. We recommend that physicians who have data for patients with DBS exceeding this duration publish their results.

Potential of an anti-bevacizumab idiotype scFv DNA-based immunization to elicit VEGF-binding antibody response.

Anti-idiotype antibodies have been considered for vaccination approaches against different diseases, including cancers. Based on that, we previously described an anti-bevacizumab idiotype monoclonal antibody, 10.D7, that revealed detectable antitumor effects on a vascular endothelial growth factor (VEGF)-dependent tumor model. Herein, we evaluated the possible applicability of a single-chain variable fragment (scFv) for the 10.D7 antibody in a gene immunization strategy. After checking that mammalian cells transfected to express the 10.D7 scFv are recognized by bevacizumab, it was explored the ability of our scFv construction, in a gene-based scheme, to elicit an immune response containing VEGF-binding antibodies. The results provide evidence that the designed 10.D7 scFv construct maintains the anti-bevacizumab idiotype features and has potential to activate an immune response recognizing VEGF.

O-GlcNAcylation in Renal (Patho)Physiology.

Kidneys maintain internal milieu homeostasis through a well-regulated manipulation of body fluid composition. This task is performed by the correlation between structure and function in the nephron. Kidney diseases are chronic conditions impacting healthcare programs globally, and despite efforts, therapeutic options for its treatment are limited. The development of chronic degenerative diseases is associated with changes in protein O-GlcNAcylation, a post-translation modification involved in the regulation of diverse cell function. O-GlcNAcylation is regulated by the enzymatic balance between O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) which add and remove GlcNAc residues on target proteins, respectively. Furthermore, the hexosamine biosynthetic pathway provides the substrate for protein O-GlcNAcylation. Beyond its physiological role, several reports indicate the participation of protein O-GlcNAcylation in cardiovascular, neurodegenerative, and metabolic diseases. In this review, we discuss the impact of protein O-GlcNAcylation on physiological renal function, disease conditions, and possible future directions in the field.

Subclinical Acute Kidney Injury in COVID-19: Possible Mechanisms and Future Perspectives.

Since the outbreak of COVID-19 disease, a bidirectional interaction between kidney disease and the progression of COVID-19 has been demonstrated. Kidney disease is an independent risk factor for mortality of patients with COVID-19 as well as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leading to the development of acute kidney injury (AKI) and chronic kidney disease (CKD) in patients with COVID-19. However, the detection of kidney damage in patients with COVID-19 may not occur until an advanced stage based on the current clinical blood and urinary examinations. Some studies have pointed out the development of subclinical acute kidney injury (subAKI) syndrome with COVID-19. This syndrome is characterized by significant tubule interstitial injury without changes in the estimated glomerular filtration rate. Despite the complexity of the mechanism(s) underlying the development of subAKI, the involvement of changes in the protein endocytosis machinery in proximal tubule (PT) epithelial cells (PTECs) has been proposed. This paper focuses on the data relating to subAKI and COVID-19 and the role of PTECs and their protein endocytosis machinery in its pathogenesis.

Albumin Expands Albumin Reabsorption Capacity in Proximal Tubule Epithelial Cells through a Positive Feedback Loop between AKT and Megalin.

Renal proximal tubule cells (PTECs) act as urine gatekeepers, constantly and efficiently avoiding urinary protein waste through receptor-mediated endocytosis. Despite its importance, little is known about how this process is modulated in physiologic conditions. Data suggest that the phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT) pathway regulates PTEC protein reabsorption. Here, we worked on the hypothesis that the physiologic albumin concentration and PI3K/AKT pathway form a positive feedback loop to expand endocytic capacity. Using LLC-PK1 cells, a model of PTECs, we showed that the PI3K/AKT pathway is required for megalin recycling and surface expression, affecting albumin uptake. Inhibition of this pathway stalls megalin at EEA1+ endosomes. Physiologic albumin concentration (0.01 mg/mL) activated AKT; this depends on megalin-mediated albumin endocytosis and requires previous activation of PI3K/mTORC2. This effect is correlated to the increase in albumin endocytosis, a phenomenon that we refer to as "albumin-induced albumin endocytosis". Mice treated with L-lysine present decreased albumin endocytosis leading to proteinuria and albuminuria associated with inhibition of AKT activity. Renal cortex explants obtained from control mice treated with MK-2206 decreased albumin uptake and promoted megalin internalization. Our data highlight the mechanism behind the capacity of PTECs to adapt albumin reabsorption to physiologic fluctuations in its filtration, avoiding urinary excretion.

May Measurement Month 2019: an analysis of blood pressure screening results from Brazil.

The aim of this study is to describe the results of the May Month Measurement (MMM) campaign implemented in Brazil, in 2019. Questionnaire data were collected and three measures of blood pressure (BP) were performed. The sample consisted of 13 476 individuals, 58.2% were white, 60.8% were women. The average age was 46.3 (18.6) years. Of all 13 476 participants, 6858 (50.9%) had hypertension defined as a systolic BP ≥140 mmHg or a diastolic BP ≥90 mmHg or being on anti-hypertensive medication. Of those with hypertension, 68.8% were aware of their diagnosis, 65.3% were on antihypertensive medication, and 36.1% had controlled BP (<140/90 mmHg). In addition, of 4479 participants on anti-hypertensive medication, 55.2% had controlled BP. The use of anti-hypertensive medication was associated with higher systolic (P < 0.001) and diastolic BP (P < 0.001) and having diabetes with higher systolic BP (P < 0.001). Previous hypertension in pregnancy was associated with higher systolic (P = 0.038) and diastolic BP (P = 0.003), and smoking was associated with higher systolic BP (P < 0.001). Lastly, obese and overweight individuals showed significantly higher systolic (P < 0.001) and diastolic (P < 0.001) BP. The Brazilian MMM19 data demonstrate that strategies to increase awareness of hypertension and a better control of the risk factors are still needed.

Role of the renin-angiotensin system in the development of severe COVID-19 in hypertensive patients.

A new form of severe acute respiratory syndrome (SARS) caused by SARS-coronavirus 2 (CoV-2), called COVID-19, has become a global threat in 2020. The mortality rate from COVID-19 is high in hypertensive patients, making this association especially dangerous. There appears to be a consensus, despite the lack of experimental data, that angiotensin II (ANG II) is linked to the pathogenesis of COVID-19. This process may occur due to acquired deficiency of angiotensin-converting enzyme 2 (ACE2), resulting in reduced degradation of ANG II. Furthermore, ANG II has a critical role in the genesis and worsening of hypertension. In this context, the idea that there is a surge in the level of ANG II with COVID-19 infection, causing multiple organ injuries in hypertensive patients becomes attractive. However, the role of other components of the renin angiotensin system (RAS) in this scenario requires elucidation. The identification of other RAS components in COVID-19 hypertension may provide both diagnostic and therapeutic benefits. Here, we summarize the pathophysiologic contributions of different components of RAS in hypertension and their possible correlation with poor outcome observed in hypertensive patients with COVID-19.

Face-to-face interactions between mothers and female infants in wild bearded capuchin monkeys (Sapajus libidinosus).

Once considered uniquely human, mother-infant face-to-face interactions (FF) were observed in a few captive primates. In these studies, FF were correlated to physical contact suggesting a mechanism mediating proximity between mother and infant, as is the case for humans. We investigated this hypothesis in wild capuchin monkeys (Sapajus libidinosus) during the first year of life of eight female infants. Data were weekly focal-day videos of infants from which we recorded FF with mothers. We expected FF would increase with infants' age (as time in contact with mothers decreased) and would more likely occur in the absence of physical contact between the dyad. There was no effect of age in the proportion of interaction time spent in FF, nor in types of FF. A quarter of FF episodes occurred in the absence of physical contact between the dyad, and in most of them physical contact was resumed following the FF. Contrary to predictions, the stability in the first year, mainly when mothers-female infants were in contact, indicates that FF act primarily promoting opportunities for affective communication and intuitive care. However, we found some supportive evidence for the hypothesis that FF regulate proximity between mother and infant, mainly in resume physical contact.

High glucose reduces megalin-mediated albumin endocytosis in renal proximal tubule cells through protein kinase B O-GlcNAcylation.

The role of albumin reabsorption in proximal tubule (PT) cells has emerged as an important factor in the genesis of albuminuria observed in the early stages of diabetes. Evidence has shown that a decrease in megalin expression could be the key mechanism in this process. In the present work, we investigated the molecular mechanism underlying the modulation of albumin endocytosis in LLC-PK1 cells, a model of PT cells. High glucose concentrations (HG) inhibited megalin expression and albumin endocytosis after 48 h of incubation. This inhibitory effect involves the entrance of glucose into PT cells through SGLT located at the luminal membrane. Once inside PT cells, glucose is diverted to the hexosamine biosynthetic pathway (HBP) increasing O-GlcNAcylation of several intracellular proteins, including PKB. This process promotes the inhibition of PKB activity measured by its phosphorylation at Thr-308 and Ser-473 and phosphorylation of specific substrates, glycogen synthase kinase 3ß (GSK3ß) and tuberous sclerosis complex 2. The decrease in PKB activity led to a decrease in megalin expression and, consequently, reducing albumin endocytosis in LLC-PK1 cells. HG did not change mammalian target of rapamycin (mTOR) C2 activity, responsible for phosphorylated PKB at Ser-473. In addition, HG activated the mTORC1/S6K pathway, but this effect was not correlated to the decrease in megalin expression or albumin endocytosis. Taken together, our data help to clarify the current understanding underlying the genesis of tubular albuminuria induced by hyperglycemia in the early stage of diabetes pathogenesis.

O-GlcNAcylation reduces proximal tubule protein reabsorption and promotes proteinuria in spontaneously hypertensive rats.

Hypertensive individuals are at greater risk for developing chronic kidney disease (CKD). Reducing proteinuria has been suggested as a possible therapeutic approach to treat CKD. However, the mechanisms underlying the development of proteinuria in hypertensive conditions are incompletely understood. Cardiac and vascular dysfunction is associated with changes in the O-GlcNAcylation pathway in hypertensive models. We hypothesized that O-GlcNAcylation is also involved in renal damage, especially development of proteinuria, associated with hypertension. Using the spontaneously hypertensive rat (SHR) model, we observed higher renal cortex O-GlcNAcylation, glutamine-fructose aminotransferase (GFAT), and O-GlcNAc transferase (OGT) protein expression, which positively correlated with proteinuria. Interestingly, this was observed in hypertensive, but not pre-hypertensive, rats. Pharmacological inhibition of GFAT decreased renal cortex O-GlcNAcylation, proteinuria, and albuminuria in SHR. Using a proximal tubule cell line, we observed that increased O-GlcNAcylation reduced megalin surface expression and albumin endocytosis in vitro, and the effects were correlated in vivo Moreover, megalin is O-GlcNAcylated both in vitro and in vivo In conclusion, our results demonstrate a new mechanism involved in hypertension-associated proteinuria.

Impact of human cytomegalovirus on glioblastoma cell viability and chemotherapy treatment.

The relationship between human cytomegalovirus (HCMV) and tumours has been extensively investigated, mainly in glioblastoma multiforme (GBM), a malignant tumour of the central nervous system with low overall survival rates. Several reports have demonstrated the presence of HCMV in GBM, although typically restricted to a low number of cells, and studies have indicated that viral proteins have the ability to dysregulate cellular processes and increase tumour malignancy. Treatment of GBM involves the use of the chemotherapeutic agents temozolomide (TMZ) and carmustine (bis-chloroethylnitrosourea, BCNU), which lead to the attachment of adducts to the DNA backbone, causing errors during replication and consequent cell death. It is known that HCMV infection can modulate DNA repair pathways, but what effects the virus may exhibit during chemotherapy are unknown. Here we approach this question by analysing HCMV infection and viral protein accumulation in GBM cell lines with different genotypes and their response to TMZ and BCNU in the presence of the virus. We demonstrate that A172, TP365MG and U251MG GBM cells are efficiently infected by both low-passage (TB40E) and high-passage (AD169) HCMV strains. However, the GBM cell lines vary widely in their permissiveness to viral gene expression and exhibit very different patterns of immediate early, early and late protein accumulation. HCMV reduces the viability of permissive GBM cells in a multiplicity-dependent manner in both the absence and presence of TMZ or BNCU. In sum, we demonstrate that GBM cell lines are equally susceptible but differentially permissive to infection by both low- and high-passage strains of HCMV. This observation not only indicates that viral replication is largely controlled by cellular factors in this system, but also provides a possible explanation for why viral gene products are only found in a subset of cells in GBM tumours. Furthermore, we conclude that the virus does not confer increased resistance to chemotherapeutic drugs in various GBM cell lines, but instead reduces tumour cell viability. These results highlight that the oncomodulatory potential of HCMV is not limited to cancer-promoting activities, but also includes adverse effects on tumour cell proliferation or survival.

Anti-bevacizumab idiotype antibody vaccination is effective in inducing vascular endothelial growth factor-binding response, impairing tumor outgrowth.

Tumors require blood supply and, to overcome this restriction, induce angiogenesis. Vascular endothelial growth factor (VEGF) plays an important role in this process, which explains the great number of antiangiogenic therapies targeting VEGF. The research and development of targeted therapy has led to the approval of bevacizumab, a humanized anti-VEGF monoclonal antibody (mAb), in clinical settings. However, side effects have been reported, usually as a consequence of bolus-dose administration of the antibody. This limitation could be circumvented through the use of anti-idiotype (Id) antibodies. In the present study, we evaluated the efficacy of an active VEGF-binding immune response generated by an anti-bevacizumab idiotype mAb, 10.D7. The 10.D7 anti-Id mAb vaccination led to detectable levels of VEGF-binding anti-anti-Id antibodies. In order to examine whether this humoral immune response could have implications for tumor development, 10.D7-immunized mice were challenged with B16-F10 tumor cells. Mice immunized with 10.D7 anti-Id mAb revealed reduced tumor growth when compared to control groups. Histological analyses of tumor sections from 10.D7-immunized mice showed increased necrotic areas, decreased CD31-positive vascular density and reduced CD68-positive cell infiltration. Our results encourage further therapeutic studies, particularly if one considers that the anti-Id therapeutic vaccination maintains stable levels of VEGF-binding antibodies, which might be useful in the control of tumor relapse.

Technetium glucose complexes as potential cancer imaging agents.

GLUT's (facilitative glucose transporters) over-expression in tumor cells has allowed the detection of several cancer types, using a glucose analogue ((18)F-FDG) with PET images, worldwide. New glucose analogs radiolabeled with (99m)Tc could be a less-expensive and more accessible alternative for diagnosis using SPECT imaging. d-Glucose ((99m)Tc-IDAG) and 2-d-deoxyglucose ((99m)Tc-AADG) organometallic complexes were proposed and studied as potential (18)F-FDG surrogates. The glucose complexes were prepared and evaluated as potential cancer imaging agents, in a melanoma tumor model. Iminodiacetic acid (IDA) and aminoacetate (AA) moieties were chosen as chelating system for radiolabeling with (99m)Tc. Tumor uptake of the formed complexes was evaluated in B16 murine cell line in vitro and in vivo in melanoma bearing C57BL/6 mice. In vitro and in vivo studies were conducted with (18)F-FDG in order to compare the uptake of (99m)Tc-glucose complexes in the tumor model. IDAG and AADG compounds were synthesized and radiolabeled with (99m)TcO4(-) to obtain the (99m)Tc-IDAG and (99m)Tc-AADG complexes in high yield and stability. In vitro cell studies showed maximum uptake at 60 min for complexes, (99m)Tc-IDAG and (99m)Tc-AADG, with 6% and 2%, respectively. Biodistribution studies showed high tumor uptake one hour post-injection, reaching tumor-to-muscle ratios of 12.1 ± 3.73 and 2.88 ± 1.40 for (99m)Tc-IDAG and (99m)Tc-AADG, respectively. SPECT and micro-SPECT-CT images acquired after the injection of (99m)Tc-IDAG showed accumulation in tumor sites, suggesting that this glucose complex would be a promising candidate for cancer imaging.

The Evolution of Surgical Technique in Spinal Cord Stimulation: A Scoping Review.

Since the advent of spinal cord stimulation (SCS), its operative technique has consistently advanced. We performed a scoping review of the literature regarding SCS operative techniques to highlight key advancements. To review, summarize, and highlight key changes in SCS implantation techniques since their inception. The authors performed a MEDLINE search inclusive of articles from 1967 to June 2023 including human and modeling studies written in English examining the role of trialing, intraoperative neuromonitoring, and surgical adaptations. Using the Rayyan platform, two reviewers performed a blinded title screen. Of the 960 articles, 197 were included in the title screen, 107 were included in the abstract review, and ultimately 69 articles met inclusion criteria. We examined the utility of trialing and found that historical controls showed significant efficacy, whereas recent results are more equivocal. We discuss the significant improvement in outcomes with intraoperative neuromonitoring for asleep SCS placement. We highlight technique improvements that led to significant reductions in infection, lead migration, and inadequate pain relief. Physicians implanting SCS systems for chronic pain management must continually refine their surgical techniques to keep up with this rapidly evolving therapy. In addition, through collaborative efforts of neuromodulators and industry, SCS is safer and more effective for patients suffering from chronic pain.

Evolution of Deep Brain Stimulation Techniques for Complication Mitigation.

Complication mitigation in deep brain stimulation has been a topic matter of much discussion in the literature. In this article, we examine how neurosurgeons as individuals and as a field generated and adapted techniques to prevent infection, lead fracture/lead migration, and suboptimal outcomes in both the acute period and longitudinally. The authors performed a MEDLINE search inclusive of articles from 1987 to June 2023 including human studies written in English. Using the Rayyan platform, two reviewers (J.P. and R.M.) performed a title screen. Of the 776 articles, 252 were selected by title screen and 172 from abstract review for full-text evaluation. Ultimately, 124 publications were evaluated. We describe the initial complications and inefficiencies at the advent of deep brain stimulation and detail changes instituted by surgeons that reduced them. Furthermore, we discuss the trend in both undesired short-term and long-term outcomes with emphasis on how surgeons recognized and modified their practice to provide safer and better procedures. This scoping review adds to the literature as a guide to both new neurosurgeons and seasoned neurosurgeons alike to understand better what innovations have been trialed over time as we embark on novel targets and neuromodulatory technologies.

A Scoping Review of Focused Ultrasound Enhanced Drug Delivery for Across the Blood-Brain Barrier for Brain Tumors.

BACKGROUND AND OBJECTIVES: Previous mechanisms of opening the blood-brain barrier (BBB) created a hypertonic environment. Focused ultrasound (FUS) has recently been introduced as a means of controlled BBB opening. Here, we performed a scoping review to assess the advances in drug delivery across the BBB for treatment of brain tumors to identify advances and literature gaps. METHODS: A review of current literature was conducted through a MEDLINE search inclusive of articles on FUS, BBB, and brain tumor barrier, including human, modeling, and animal studies written in English. Using the Rayyan platform, 2 reviewers (J.P and C.Y) identified 967 publications. 224 were chosen to review after a title screen. Ultimately 98 were reviewed. The scoping review was designed to address the following questions: (1) What FUS technology improvements have been made to augment drug delivery for brain tumors? (2) What drug delivery improvements have occurred to ensure better uptake in the target tissue for brain tumors? RESULTS: Microbubbles (MB) with FUS are used for BBB opening (BBBO) through cavitation to increase its permeability. Drug delivery into the central nervous system can be combined with MB to enhance transport of therapeutic agents to target brain tissue resulting in suppression of tumor growth and prolonging survival rate, as well as reducing systemic toxicity and degradation rate. There is accumulating evidence demonstrating that drug delivery through BBBO with FUS-MB improves drug concentrations and provides a better impact on tumor growth and survival rates, compared with drug-only treatments. CONCLUSION: Here, we review the role of FUS in BBBO. Identified gaps in the literature include impact of tumor microenvironment and extracellular space, improved understanding and control of MB and drug delivery, further work on ideal pharmacologics for delivery, and clinical use.

Toll like receptor 4 mediates the inhibitory effect of SARS-CoV-2 spike protein on proximal tubule albumin endocytosis.

Tubular proteinuria is a common feature in COVID-19 patients, even in the absence of established acute kidney injury. SARS-CoV-2 spike protein (S protein) was shown to inhibit megalin-mediated albumin endocytosis in proximal tubule epithelial cells (PTECs). Angiotensin-converting enzyme type 2 (ACE2) was not directly involved. Since Toll-like receptor 4 (TLR4) mediates S protein effects in various cell types, we hypothesized that TLR4 could be participating in the inhibition of PTECs albumin endocytosis elicited by S protein. Two different models of PTECs were used: porcine proximal tubule cells (LLC-PK1) and human embryonic kidney cells (HEK-293). S protein reduced Akt activity by specifically inhibiting of threonine 308 (Thr308) phosphorylation, a process mediated by phosphoinositide-dependent kinase 1 (PDK1). GSK2334470, a PDK1 inhibitor, decreased albumin endocytosis and megalin expression mimicking S protein effect. S protein did not change total TLR4 expression but decreased its surface expression. LPS-RS, a TLR4 antagonist, also counteracted the effects of the S protein on Akt phosphorylation at Thr308, albumin endocytosis, and megalin expression. Conversely, these effects of the S protein were replicated by LPS, an agonist of TLR4. Incubation of PTECs with a pseudovirus containing S protein inhibited albumin endocytosis. Null or VSV-G pseudovirus, used as control, had no effect. LPS-RS prevented the inhibitory impact of pseudovirus containing the S protein on albumin endocytosis but had no influence on virus internalization. Our findings demonstrate that the inhibitory effect of the S protein on albumin endocytosis in PTECs is mediated through TLR4, resulting from a reduction in megalin expression.

[(99m)Tc(CO)(3)]-radiolabeled bevacizumab: in vitro and in vivo evaluation in a melanoma model.

INTRODUCTION: Vascular endothelial growth factor (VEGF) is one of the classic factors to tumor-induced angiogenesis in several tumor types, including melanoma. Bevacizumab, a monoclonal antibody against VEGF, could be used as an imaging tool in preclinical studies. OBJECTIVE: To radiolabel bevacizumab with [(99m)Tc(CO)3(OH2)3](+) and evaluate it in vivo and in vitro for melanoma imaging properties. METHODS: Bevacizumab was radiolabeled with [(99m)Tc(CO)3(OH2)3](+) ion in saline. The radiochemical stability of the labeled antibody was assessed. The biodistribution and scintigraphy imaging of the radiolabeled antibody were evaluated in normal C57BL/6J mice and in C57BL/6J mice bearing murine B16F1 melanoma tumors. Immunoreactivity of bevacizumab to murine tumors was determined from direct immunofluorescence and immunoblotting assays. RESULTS: We demonstrate that (99m)Tc(CO)3-bevacizumab was stable. In vivo biodistribution studies revealed that tumor uptake of (99m)Tc(CO)3-bevacizumab was 2.64 and 2.51 %ID/g at 4 and 24 h postinjection. Scintigraphy image studies showed tumor selective uptake of (99m)Tc(CO)3-bevacizumab in the tumor-bearing mice. This affinity was confirmed by immunoassays performed on B16F10 tumor samples. CONCLUSIONS: (99m)Tc(CO)3-bevacizumab could be used as an approach for tumor nuclear imaging in preclinical studies. This should be useful to provide insights into the angiogenic stimulus before and after chemotherapy, which might help improve current antitumor therapy.

Inhibition of SGLT2 co-transporter by dapagliflozin ameliorates tubular proteinuria and tubule-interstitial injury at the early stage of diabetic kidney disease.

Diabetic kidney disease (DKD) is characterized by progressive impairment of kidney function. It has been postulated that tubule-interstitial injury, associated with tubular albuminuria, precedes glomerular damage in the early stage of DKD. Here, we wanted to determine if the development of tubule-interstitial injury at the early stage of DKD implies modulation of megalin-mediated protein reabsorption in proximal tubule epithelial cells (PTECs) by SGLT2-dependent high glucose influx. Rats with streptozotocin (STZ)-induced diabetes were treated or not with dapagliflozin (DAPA) for 8 weeks. Four experimental groups were generated: (1) CONT, control; (2) DAPA, rats treated with DAPA; (3) STZ, diabetic rats; (4) STZ + DAPA, diabetic rats treated with DAPA. No changes in glomerular structure and function were observed. The STZ group presented proteinuria and albuminuria associated with an increase in the fractional excretion of proteins. A positive correlation between glycemia and proteinuria was found. These phenomena were linked to a decrease in luminal and total megalin expression and, consequently, in albumin reabsorption in PTECs. We also observed tubule-interstitial injury characterized by an increase in urinary tubular injury biomarkers and changes in tubular histomorphometry parameters. In addition, inverse correlations were found between cortical albumin uptake and tubule-interstitial injury or glycemia. All these modifications were attenuated in the STZ + DAPA group. These results suggest that SGLT2-dependent high glucose influx into PTECs promotes a harmful effect on the PTECs, leading to the development of tubular albuminuria and tubule-interstitial injury preceding glomerular damage. These results expand current knowledge on the renoprotective effects of gliflozins.