Targeted Therapies in Cardiovascular and Kidney Diseases

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (20 August 2023) | Viewed by 10455

Special Issue Editors


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Guest Editor
1. Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon
2. Michigan Medicine, Neuronetwork for Emerging Medicine, University of Michigan, Ann Arbor, MI 48109, USA
3. Faculty of Basic and Biomedical Sciences, Université de Paris, Sorbonne Paris Cité, 75015 Paris, France
Interests: diabetes mellitus; diabetic neuropathy; diabetic nephropathy; diabetic cardiomyopathy; diabetes-induced cancer

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Guest Editor
Department of Pharmaceutics, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
Interests: drug delivery systems; peritoneal targeting; gene delivery; tissue clearing method; pharmacokinetics

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Guest Editor
Department of Neurology, University of Mississippi Medical Center, 2500 N State St., Room N321-2, Jackson, MS 39216, USA
Interests: targeted drug delivery; therapeutics peptides; tumor; drug delivery during pregnancy

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Guest Editor
Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon
Interests: diabetes mellitus; pharmacotherapeutics; diabetic kidney disease; netosis

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Guest Editor
1. Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
2. Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon
Interests: diabetic kidney disease; diabetes mellitus; hepatopancreaticobiliary surgery; liver cancer; pancreatic cancer

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Guest Editor Assistant
1. Faculty of Medical Sciences, Lebanese University, Beirut 1003, Lebanon
2. Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon
Interests: diabetes mellitus; oncology; diabetes-induced cancer; diabetic kidney disease

Special Issue Information

Dear Colleagues,

Despite the various scientific and medical efforts invested into understanding the multitude of known kidney diseases, direct therapies to treat some of the most prevalent kidney disorders are yet to be identified. Furthermore, even though targeted therapies such as tyrosine kinase inhibitors, VEGF inhibitors, mTOR blockers and others are currently being used to tackle the progression of advanced kidney cancer, according to the American Cancer Society, these targeted therapies “Sometimes work when standard chemo drugs don’t “, but “it doesn’t seem that any of these drugs can actually cure kidney cancer”. Therefore, scientists have started focusing their research on the successful use of targeted therapies for kidney diseases, with multiple studies showing promise. In addition, targeted drug delivery systems have attracted attention as they comprise the systemic delivery of a drug carrier system to specific cell types, tissues or organs. Moreover, drugs need to be personalized to each patient; however, most new oral-targeted drugs are still administered in a cookie-cutter fixed-dose approach. Ultimately, patients should not only be treated with the right drug, but also at the right dose.

In this Special Issue of Pharmaceutics on “Targeted Therapies in Kidney Diseases”, attempts to describe, discover and repurpose drug treatments for nephropathy, nephrotic syndrome, nephritic syndrome, CKD, AKI, polycystic kidney disease, Alport syndrome and kidney cancer will be highlighted. Original research articles, review papers and communications are welcome.

Dr. Assaad A. Eid
Prof. Dr. Koyo Nishida
Dr. Gene L. Bidwell, III
Dr. Rachel Njeim
Dr. Antony F. Haddad
Guest Editors

Rashad Nawfal
Guest Editor Assistant

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Keywords

  • diabetic nephropathy
  • Alport syndrome
  • polycystic kidney disease
  • nephrotic syndrome
  • nephritic syndrome
  • chronic kidney disease
  • acute kidney injury
  • renal cell carcinoma
  • kidney cancer
  • targeted therapy
  • drug repurposing
  • novel targets
  • targeted delivery system

Published Papers (6 papers)

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Research

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14 pages, 5689 KiB  
Article
Granulocyte Colony-Stimulating Factor Improves Endothelial Progenitor Cell-Mediated Neovascularization in Mice with Chronic Kidney Disease
by Shao-Yu Tang, Yi-Chin Lee, Chien-Wei Tseng, Po-Hsun Huang, Ko-Lin Kuo and Der-Cherng Tarng
Pharmaceutics 2023, 15(10), 2380; https://doi.org/10.3390/pharmaceutics15102380 - 25 Sep 2023
Viewed by 964
Abstract
Patients with chronic kidney disease (CKD) have a higher prevalence of peripheral arterial disease (PAD), and endothelial progenitor cells (EPCs) play a pivotal role. We examined the impact of granulocyte colony-stimulating factor (G-CSF) on EPC function in response to tissue ischemia. Eight-week-old male [...] Read more.
Patients with chronic kidney disease (CKD) have a higher prevalence of peripheral arterial disease (PAD), and endothelial progenitor cells (EPCs) play a pivotal role. We examined the impact of granulocyte colony-stimulating factor (G-CSF) on EPC function in response to tissue ischemia. Eight-week-old male C57BL/6J male mice were divided into sham operation and subtotal nephrectomy (SNx) groups, received hindlimb ischemic operation after seven weeks, then randomly received G-CSF or PBS intervention for four weeks with weekly follow-ups. SNx mice had significantly reduced limb reperfusion, decreased plasma EPC mobilization, and impaired angiogenesis in ischemic hindlimbs compared to the control group. However, G-CSF increased IL-10 and reversed these adverse changes. Additionally, ischemia-associated protein expressions, including IL-10, phospho-STAT3, VEGF, and phospho-eNOS, were significantly downregulated in the ischemic hindlimbs of SNx mice versus control, but these trends were reversed by G-CSF. Furthermore, in cultured EPCs, G-CSF significantly attenuated the decrease in EPC function initiated by indoxyl sulfate through IL-10. Overall, we discovered that G-CSF can improve EPC angiogenic function through a hypoxia/IL-10 signaling cascade and impede neovascular growth in response to ischemia of SNx mice. Our results highlight G-CSF’s potential to restore angiogenesis in CKD patients with PAD via EPC-based methods. Full article
(This article belongs to the Special Issue Targeted Therapies in Cardiovascular and Kidney Diseases)
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11 pages, 1338 KiB  
Communication
The Mineralocorticoid Receptor on Smooth Muscle Cells Promotes Tacrolimus-Induced Renal Injury in Mice
by Stefanny M. Figueroa, Jean-Philippe Bertocchio, Toshifumi Nakamura, Soumaya El-Moghrabi, Frédéric Jaisser and Cristián A. Amador
Pharmaceutics 2023, 15(5), 1373; https://doi.org/10.3390/pharmaceutics15051373 - 29 Apr 2023
Cited by 1 | Viewed by 1456
Abstract
Tacrolimus (Tac) is a calcineurin inhibitor commonly used as an immunosuppressor after solid organ transplantation. However, Tac may induce hypertension, nephrotoxicity, and an increase in aldosterone levels. The activation of the mineralocorticoid receptor (MR) is related to the proinflammatory status at the renal [...] Read more.
Tacrolimus (Tac) is a calcineurin inhibitor commonly used as an immunosuppressor after solid organ transplantation. However, Tac may induce hypertension, nephrotoxicity, and an increase in aldosterone levels. The activation of the mineralocorticoid receptor (MR) is related to the proinflammatory status at the renal level. It modulates the vasoactive response as they are expressed on vascular smooth muscle cells (SMC). In this study, we investigated whether MR is involved in the renal damage generated by Tac and if the MR expressed in SMC is involved. Littermate control mice and mice with targeted deletion of the MR in SMC (SMC-MR-KO) were administered Tac (10 mg/Kg/d) for 10 days. Tac increased the blood pressure, plasma creatinine, expression of the renal induction of the interleukin (IL)-6 mRNA, and expression of neutrophil gelatinase-associated lipocalin (NGAL) protein, a marker of tubular damage (p < 0.05). Our study revealed that co-administration of spironolactone, an MR antagonist, or the absence of MR in SMC-MR-KO mice mitigated most of the unwanted effects of Tac. These results enhance our understanding of the involvement of MR in SMC during the adverse reactions of Tac treatment. Our findings provided an opportunity to design future studies considering the MR antagonism in transplanted subjects. Full article
(This article belongs to the Special Issue Targeted Therapies in Cardiovascular and Kidney Diseases)
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19 pages, 4420 KiB  
Article
SGLT2 Inhibitor—Dapagliflozin Attenuates Diabetes-Induced Renal Injury by Regulating Inflammation through a CYP4A/20-HETE Signaling Mechanism
by Batoul Dia, Sahar Alkhansa, Rachel Njeim, Sarah Al Moussawi, Theresa Farhat, Antony Haddad, Mansour E. Riachi, Rashad Nawfal, William S. Azar and Assaad A. Eid
Pharmaceutics 2023, 15(3), 965; https://doi.org/10.3390/pharmaceutics15030965 - 16 Mar 2023
Cited by 2 | Viewed by 2077
Abstract
Diabetic kidney disease (DKD) is a serious complication of diabetes, affecting millions of people worldwide. Inflammation and oxidative stress are key contributors to the development and progression of DKD, making them potential targets for therapeutic interventions. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have emerged [...] Read more.
Diabetic kidney disease (DKD) is a serious complication of diabetes, affecting millions of people worldwide. Inflammation and oxidative stress are key contributors to the development and progression of DKD, making them potential targets for therapeutic interventions. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a promising class of drugs, with evidence demonstrating that they can improve renal outcomes in people with diabetes. However, the exact mechanism by which SGLT2i exert their renoprotective effects is not yet fully understood. This study demonstrates that dapagliflozin treatment attenuates renal injury observed in type 2 diabetic mice. This is evidenced by the reduction in renal hypertrophy and proteinuria. Furthermore, dapagliflozin decreases tubulointerstitial fibrosis and glomerulosclerosis by mitigating the generation of reactive oxygen species and inflammation, which are activated through the production of CYP4A-induced 20-HETE. Our findings provide insights onto a novel mechanistic pathway by which SGLT2i exerts their renoprotective effects. Overall, and to our knowledge, the study provides critical insights into the pathophysiology of DKD and represents an important step towards improving outcomes for people with this devastating condition. Full article
(This article belongs to the Special Issue Targeted Therapies in Cardiovascular and Kidney Diseases)
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Review

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19 pages, 1234 KiB  
Review
Tailoring Treatment in Cardiovascular Diseases: The Role of Targeted Therapies
by Razan Dankar, Jad Wehbi and Marwan M. Refaat
Pharmaceutics 2024, 16(4), 461; https://doi.org/10.3390/pharmaceutics16040461 - 26 Mar 2024
Viewed by 725
Abstract
Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality around the globe. To address this public health burden, innovative therapeutic agents are being developed to specifically target molecular and genetic markers. Various therapeutic modalities have been implemented, including vaccines, monoclonal or [...] Read more.
Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality around the globe. To address this public health burden, innovative therapeutic agents are being developed to specifically target molecular and genetic markers. Various therapeutic modalities have been implemented, including vaccines, monoclonal or bispecific antibodies, and gene-based therapies. Such drugs precisely target the underlying disease pathophysiology, aiming at notable molecules such as lipid metabolism regulators, proinflammatory cytokines, and growth factors. This review focuses on the latest advancements in different targeted therapies. It provides an insightful overview of the current landscape of targeted cardiovascular therapies, highlighting promising strategies with potential to transform the treatment of CVDs into an era of precision medicine. Full article
(This article belongs to the Special Issue Targeted Therapies in Cardiovascular and Kidney Diseases)
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24 pages, 1159 KiB  
Review
Unraveling the Crosstalk between Lipids and NADPH Oxidases in Diabetic Kidney Disease
by Rachel Njeim, Sahar Alkhansa and Alessia Fornoni
Pharmaceutics 2023, 15(5), 1360; https://doi.org/10.3390/pharmaceutics15051360 - 28 Apr 2023
Cited by 3 | Viewed by 1689
Abstract
Diabetic kidney disease (DKD) is a serious complication of diabetes mellitus and a leading cause of end-stage renal disease. Abnormal lipid metabolism and intrarenal accumulation of lipids have been shown to be strongly correlated with the development and progression of diabetic kidney disease [...] Read more.
Diabetic kidney disease (DKD) is a serious complication of diabetes mellitus and a leading cause of end-stage renal disease. Abnormal lipid metabolism and intrarenal accumulation of lipids have been shown to be strongly correlated with the development and progression of diabetic kidney disease (DKD). Cholesterol, phospholipids, triglycerides, fatty acids, and sphingolipids are among the lipids that are altered in DKD, and their renal accumulation has been linked to the pathogenesis of the disease. In addition, NADPH oxidase-induced production of reactive oxygen species (ROS) plays a critical role in the development of DKD. Several types of lipids have been found to be tightly linked to NADPH oxidase-induced ROS production. This review aims to explore the interplay between lipids and NADPH oxidases in order to provide new insights into the pathogenesis of DKD and identify more effective targeted therapies for the disease. Full article
(This article belongs to the Special Issue Targeted Therapies in Cardiovascular and Kidney Diseases)
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16 pages, 1169 KiB  
Review
The Pillars for Renal Disease Treatment in Patients with Type 2 Diabetes
by Jessica Kearney and Luigi Gnudi
Pharmaceutics 2023, 15(5), 1343; https://doi.org/10.3390/pharmaceutics15051343 - 27 Apr 2023
Cited by 6 | Viewed by 2857
Abstract
The diabetes epidemic and the increasing number of patients with diabetic chronic vascular complications poses a significant challenge to health care providers. Diabetic kidney disease is a serious diabetes-mediated chronic vascular complication and represents a significant burden for both patients and society in [...] Read more.
The diabetes epidemic and the increasing number of patients with diabetic chronic vascular complications poses a significant challenge to health care providers. Diabetic kidney disease is a serious diabetes-mediated chronic vascular complication and represents a significant burden for both patients and society in general. Diabetic kidney disease not only represents the major cause of end stage renal disease but is also paralleled by an increase in cardiovascular morbidity and mortality. Any interventions to delay the development and progression of diabetic kidney disease are important to reduce the associated cardiovascular burden. In this review we will discuss five therapeutic tools for the prevention and treatment of diabetic kidney disease: drugs inhibiting the renin–angiotensin–aldosterone system, statins, the more recently recognized sodium-glucose co-transporter-2 inhibitors, glucagon-like peptide 1 agonists, and a novel non-steroidal selective mineralocorticoid receptor antagonist. Full article
(This article belongs to the Special Issue Targeted Therapies in Cardiovascular and Kidney Diseases)
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