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Recent Advances in Molecular Mechanisms Underlying Kidney Diseases: Pathophysiology and Therapeutic Targets

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 April 2024) | Viewed by 6048

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Special Issue Editor

Dr. George J. Dugbartey

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Guest Editor

Department of Surgery, London Health Sciences Center, University of Western Ontario, London, ON N6A 5C1, Canada
Interests: kidney diseases; pharmacotherapy; kidney transplantation; cellular and molecular mechanisms; renal protection

Special Issue Information

Dear Colleagues,

Kidney diseases remain a major public health concern associated with the increasing morbidity and mortality of millions of people globally. Unfortunately, the prevalence of kidney diseases has increased significantly in recent times. The hallmarks of this important human pathology include the excessive accumulation and deposition of extracellular matrix, mesangiolysis, glomerular basement membrane thickening, tubulointerstitial fibrosis and many more, which eventually lead to loss of kidney function. As the pathogenesis of different forms of kidney diseases is multifactorial, several experimental models have recently been developed to mimic clinical situations and provide a mechanistic understanding of the various pathologies of kidney diseases, with the ultimate goal of identifying and developing potential therapeutic targets. These experimental models have identified several molecular mechanisms underlying various forms of kidney diseases. These mechanisms include:

PI3K/Akt/mTOR pathway;
Jak/Stat and inflammatory signaling pathways;
Induction of oxidative stress and apoptotic pathways;
Upregulation of renal transforming growth factor beta-1 expression;
Activation of fibroblast and renin-angiotensin-aldosterone system;
Mitochondrial dysfunction and depletion of adenosine triphosphate.

Targeting various molecular mechanisms underlying the pathophysiology of the different forms of kidney diseases has shown to be beneficial, and offers a huge potential to be explored that is amenable to novel therapies. This Special Issue focuses on recent research developments in the pathophysiology of kidney diseases and their therapeutic targets for diagnosis and treatment.

Original papers, review articles, and perspectives from experts in the field are welcome.

Dr. George J. Dugbartey
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

kidney diseases
pathophysiology
molecular mechanisms
therapeutic targets
acute kidney injury
chronic kidney disease
polycystic kidney disease
end-stage renal disease
iga nephropathy
diabetic nephropathy
hypertensive nephropathy
renal cancer
kidney infarction
kidney infection
kidney failure
kidney stones
renal tubular acidosis
renal artery stenosis
acute tubular necrosis
glomerulopathy
interstitial nephritis
nephrotic syndrome
simple kidney cyst

Published Papers (6 papers)

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Research

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14 pages, 1520 KiB

Open AccessArticle

Hypervolemia in Dialysis Patients Impairs STAT3 Signaling and Upregulates miR-142-3p: Effects on IL-10 and IL-6

by Christof Ulrich, Roman Fiedler, Eva Herberger, Zeynep Canim, Silke Markau and Matthias Girndt

Int. J. Mol. Sci. 2024, 25(7), 3719; https://doi.org/10.3390/ijms25073719 - 27 Mar 2024

Viewed by 589

Abstract

Fluid overload in hemodialysis patients (HD) has been proven to be associated with inflammation. Elevated levels of the pro-inflammatory cytokine interleukin-6 (IL-6) appear to be inadequately counterbalanced by the anti-inflammatory cytokine interleukin-10 (IL-10). We initiated a cross-sectional study enrolling 40 HD patients who were categorized by a bioimpedance measurement in normovolemic (N; 23) and hypervolemic (H; 17) groups to test whether IL-10- and IL-6-related signal transduction pathways (signal transducer of transcript 3: STAT3) and/or a post-transcriptional regulating mechanism (miR-142) are impaired by hypervolemia. IL-10/IL-6 transcript and protein production by PBMCs (peripheral blood mononuclear cells) were determined. Phospho-flow cytometry was used to detect the phosphorylated forms of STAT3 (pY705 and pS727). miR-142-3p/5p levels were detected by qPCR. Hypervolemic patients were older, more frequently had diabetes, and showed higher CRP levels. IL-10 transcripts were elevated in H patients but not IL-10 protein levels. In spite of the elevated mRNA expression of the suppressor of cytokine expression 3 (SOCS3), IL-6 mRNA and protein expression were increased in immune cells of H patients. The percentage of cells staining positive for STAT3 (pY705) were comparable in both groups; in STAT3 (pS727), however, the signal needed for full transactivation was decreased in H patients. miR-142-3p, a proven target of IL-10 and IL-6, was significantly elevated in H patients. Insufficient phosphorylation of STAT3 may impair inflammatory and anti-inflammatory cytokine signaling. How far degradative mechanisms induced by elevated miR-142-3p levels contribute to an inefficient anti-inflammatory IL-10 signaling remains elusive. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms Underlying Kidney Diseases: Pathophysiology and Therapeutic Targets)

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8 pages, 1574 KiB

Open AccessCommunication

A Transcriptome Array-Based Approach to Link SGLT-2 and Intrarenal Complement C5 Synthesis in Diabetic Nephropathy

by Peter Korsten and Björn Tampe

Int. J. Mol. Sci. 2023, 24(23), 17066; https://doi.org/10.3390/ijms242317066 - 02 Dec 2023

Viewed by 810

Abstract

Diabetic nephropathy is a common microvascular complication of diabetes mellitus. It is characterized by progressive chronic kidney disease (CKD) with decline of kidney function by hyperfiltration. On a mechanistic level, activation of the complement system has been implicated in the pathogenesis of diabetic nephropathy. Therefore, here we pursued a transcriptome array-based approach to link intrarenal SGLT-2 and the synthesis of distinct complement components in diabetic nephropathy. Publicly available datasets for SLC5A2 (encoding SGLT-2) and complement system components were extracted specifically from microdissected tubulointerstitial (healthy controls: n = 31, diabetic nephropathy: n = 17) and glomerular compartments (healthy controls: n = 21, diabetic nephropathy: n = 12). First, we compared tubulointerstitial and glomerular log₂ SLC5A2 mRNA expression levels and confirmed a predominant synthesis within the tubulointerstitial compartment. Among various complement components and receptors, the only significant finding was a positive association between SLC5A2 and the tubulointerstitial synthesis of the complement component C5 in diabetic nephropathy (p = 0.0109). Finally, intrarenal expression of SLC5A2 was associated predominantly with pathways involved in metabolic processes. Interestingly, intrarenal complement C5 synthesis was also associated with enrichment of metabolic signaling pathways, overlapping with SLC5A2 for “metabolism” and “biological oxidations”. These observations could be of relevance in the pathogenesis of diabetic nephropathy and implicate a mechanistic link between SGLT-2 and intrarenal complement synthesis. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms Underlying Kidney Diseases: Pathophysiology and Therapeutic Targets)

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14 pages, 1982 KiB

Open AccessArticle

Effects of Exercise Training on Mitochondrial Fatty Acid β-Oxidation in the Kidneys of Dahl Salt-Sensitive Rats

by Asako Namai-Takahashi, Junta Takahashi, Yoshiko Ogawa, Akihiro Sakuyama, Lusi Xu, Takahiro Miura, Masahiro Kohzuki and Osamu Ito

Int. J. Mol. Sci. 2023, 24(21), 15601; https://doi.org/10.3390/ijms242115601 - 26 Oct 2023

Viewed by 882

Abstract

Exercise training (Ex) has anti-hypertensive and renal protective effects. In this study, we investigate the effects of Ex on mitochondrial fatty acid metabolism in the kidneys of Dahl salt-sensitive (Dahl-S) rats fed a high-salt (HS) diet. Eight-week-old, male Dahl-S rats were divided into three groups: (1) normal-salt diet, sedentary (NS-Sed), (2) HS diet, sedentary (HS-Sed), and (3) HS-Ex. The NS and HS groups were fed a diet containing 0.6% and 8% NaCl, respectively. The HS-Ex group performed treadmill running for 8 weeks (5 days/week; 60 min/day at 16–20 m/min, 0% gradient). Renal function and the expression of enzymes and regulators of β-oxidation and electron transport chain (ETC) complexes were assessed. HS increased systolic blood pressure and proteinuria, and Ex ameliorated these defects. HS also reduced creatinine clearance, and Ex ameliorated it. HS reduced the renal expression of enzymes of β-oxidation (carnitine palmitoyltransferase type I (CPTI) and acyl-CoA dehydrogenases (CADs)) and the related transcription factors peroxisome proliferator-activated receptor α (PPARα) and PPARγ-coactivator-1α (PGC-1α), and Ex restored this. HS also reduced the renal expression of enzymes in ETC complexes, and Ex restored this expression. Ex ameliorates HS-induced renal damage by upregulating enzymes involved in fatty acid β-oxidation and ETC complexes via increases in PPAR-α and PGC-1α expressions in the kidneys of Dahl-S rats. These results suggest that Ex may have beneficial effects on HS-induced mitochondrial dysfunction in the kidney. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms Underlying Kidney Diseases: Pathophysiology and Therapeutic Targets)

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14 pages, 2435 KiB

Open AccessArticle

Static Cold Storage with Mitochondria-Targeted Hydrogen Sulfide Donor Improves Renal Graft Function in an Ex Vivo Porcine Model of Controlled Donation-after-Cardiac-Death Kidney Transplantation

by George J. Dugbartey, Smriti Juriasingani, Mahms Richard-Mohamed, Andrew Rasmussen, Max Levine, Winnie Liu, Aaron Haig, Matthew Whiteman, Jacqueline Arp, Patrick P.W. Luke and Alp Sener

Int. J. Mol. Sci. 2023, 24(18), 14017; https://doi.org/10.3390/ijms241814017 - 13 Sep 2023

Cited by 2 | Viewed by 1026

Abstract

The global donor kidney shortage crisis has necessitated the use of suboptimal kidneys from donors-after-cardiac-death (DCD). Using an ex vivo porcine model of DCD kidney transplantation, the present study investigates whether the addition of hydrogen sulfide donor, AP39, to University of Wisconsin (UW) solution improves graft quality. Renal pedicles of male pigs were clamped in situ for 30 min and the ureters and arteries were cannulated to mimic DCD. Next, both donor kidneys were nephrectomized and preserved by static cold storage in UW solution with or without AP39 (200 nM) at 4 °C for 4 h followed by reperfusion with stressed autologous blood for 4 h at 37 °C using ex vivo pulsatile perfusion apparatus. Urine and arterial blood samples were collected hourly during reperfusion. After 4 h of reperfusion, kidneys were collected for histopathological analysis. Compared to the UW-only group, UW+AP39 group showed significantly higher pO₂ (p < 0.01) and tissue oxygenation (p < 0.05). Also, there were significant increases in urine production and blood flow rate, and reduced levels of urine protein, serum creatinine, blood urea nitrogen, plasma Na⁺ and K⁺, as well as reduced intrarenal resistance in the UW+AP39 group compared to the UW-only group. Histologically, AP39 preserved renal structure by reducing the apoptosis of renal tubular cells and immune cell infiltration. Our finding could lay the foundation for improved graft preservation and reduce the increasingly poor outcomes associated with DCD kidney transplantation. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms Underlying Kidney Diseases: Pathophysiology and Therapeutic Targets)

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8 pages, 2637 KiB

Open AccessCommunication

Discrepancy Analysis between Histology and Molecular Diagnoses in Kidney Allograft Biopsies: A Single-Center Experience

by Liye Suo, Martha Caicedo Murillo, Brian Gallay and Reut Hod-Dvorai

Int. J. Mol. Sci. 2023, 24(18), 13817; https://doi.org/10.3390/ijms241813817 - 07 Sep 2023

Cited by 2 | Viewed by 713

Abstract

Histology diagnosis is essential for the monitoring and management of kidney transplant patients. Nowadays, the accuracy and reproducibility of histology have been criticized when compared with molecular microscopy diagnostic system (MMDx). Our cohort included 95 renal allograft biopsies with both histology and molecular diagnoses. Discrepancies between histology and molecular diagnosis were assessed for each biopsy. Among the 95 kidney allograft biopsies, a total of 6 cases (6%) showed clear (n = 4) or borderline (n = 2) discrepancies between histology and molecular diagnoses. Four out of the six (67%) were cases with pathologically and clinically confirmed active infections that were diagnosed as mild to moderate T-cell-mediated rejection (TCMR) with MMDx. Two cases showed pathological changes that were not sufficient to make a definitive diagnosis of active rejection via histology, while MMDx results showed antibody-mediated rejection (ABMR). In addition, there were six cases with recurrent or de novo glomerular diseases diagnosed only via histology. All other biopsy results were in an agreement. Our results indicate that histology diagnosis of kidney allograft biopsy is superior to molecular diagnosis in the setting of infections and glomerular diseases; however, MMDx can provide helpful information to confirm the diagnosis of active ABMR. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms Underlying Kidney Diseases: Pathophysiology and Therapeutic Targets)

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Review

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27 pages, 915 KiB

Open AccessReview

Molecular Mechanisms of Oxidative Stress in Acute Kidney Injury: Targeting the Loci by Resveratrol

by Hina Rashid, Abdulmajeed Jali, Mohammad Suhail Akhter and Sayed Aliul Hasan Abdi

Int. J. Mol. Sci. 2024, 25(1), 3; https://doi.org/10.3390/ijms25010003 - 19 Dec 2023

Viewed by 1422

Abstract

Reactive oxygen species are a group of cellular molecules that stand as double-edged swords, their good and bad being discriminated by a precise balance. Several metabolic reactions in the biological system generate these molecules that interact with cellular atoms to regulate functions ranging from cell homeostasis to cell death. A prooxidative state of the cell concomitant with decreased clearance of such molecules leads to oxidative stress, which contributes as a prime pathophysiological mechanism in various diseases including renal disorders, such as acute kidney injury. However, targeting the generation of oxidative stress in renal disorders by an antioxidant, resveratrol, is gaining considerable therapeutic importance and is known to improve the condition in preclinical studies. This review aims to discuss molecular mechanisms of oxidative stress in acute kidney injury and its amelioration by resveratrol. The major sources of data were PubMed and Google Scholar, with studies from the last five years primarily included, with significant earlier data also considered. Mitochondrial dysfunction, various enzymatic reactions, and protein misfolding are the major sources of reactive oxygen species in acute kidney injury, and interrupting these loci of generation or intersection with other cellular components by resveratrol can mitigate the severity of the condition. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms Underlying Kidney Diseases: Pathophysiology and Therapeutic Targets)

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