Cellular and Molecular Basis in Chronic Kidney Disease

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: 25 November 2024 | Viewed by 3502

Special Issue Editor


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Guest Editor
Department of Medicine, College of Medicine and Life Sciences, The University of Toledo, Toledo, OH 43614, USA
Interests: chronic kidney disease; cardiovascular disease; vascular calcification; atherosclerosis

Special Issue Information

Dear Colleagues,

Chronic kidney disease (CKD) corresponds to a condition involving an alteration in kidney capacity persisting for three months or more with eventual loss of function over time. CKD can be divided into five specific stages, with factors such as glomerular filtration rate (GFR) and albuminuria serving as criteria for categorization. One of the central pathways involved in the pathogenesis of CKD is the renin–angiotensin–aldosterone system (RAAS). When this pathway is activated, it induces contraction of the glomerular afferent arterioles, resulting in worsening renal ischemia which ultimately diminishes glomerular filtration capacity. Of the enzymes and peptides involved, aldosterone has been identified as causing pathological effects leading to kidney inflammation and fibrosis. In the CKD model, aldosterone production has been shown to be elevated and involved in the formation of fibroblast cells, renal fibrosis, and initiation of hypertension, all of which cause sodium overload. Collectively, these effects manifest into worsening renal damage. Another fundamental aspect found present in every stage of CKD is renal fibrosis and one important mediator of myofibroblast activation is TGF-B1. Collectively, RAAS, TGF-B1, and other factors such as vascular calcification and uremic toxins are known to be involved in CKD, causing worsening renal inflammation and fibrosis, both of which diminish renal capacity and function. This Special Issue on CKD aims to recruit original papers, reviews, and communication that enhance the understanding of cellular and molecular mechanisms involved in the pathophysiology of CKD.

Dr. Prabhatchandra Dube
Guest Editor

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Keywords

  • CKD
  • renal inflammation
  • renal fibrosis
  • RAAS
  • aldosterone
  • TGF-B1
  • uremic toxins
  • hypertension
  • GFR
  • albuminuria

Published Papers (3 papers)

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18 pages, 5663 KiB  
Article
AUP1 Regulates the Endoplasmic Reticulum-Associated Degradation and Polyubiquitination of NKCC2
by Nadia Frachon, Sylvie Demaretz, Elie Seaayfan, Lydia Chelbi, Dalal Bakhos-Douaihy and Kamel Laghmani
Cells 2024, 13(5), 389; https://doi.org/10.3390/cells13050389 - 24 Feb 2024
Cited by 1 | Viewed by 1427
Abstract
Inactivating mutations of kidney Na-K-2Cl cotransporter NKCC2 lead to antenatal Bartter syndrome (BS) type 1, a life-threatening salt-losing tubulopathy. We previously reported that this serious inherited renal disease is linked to the endoplasmic reticulum-associated degradation (ERAD) pathway. The purpose of this work is [...] Read more.
Inactivating mutations of kidney Na-K-2Cl cotransporter NKCC2 lead to antenatal Bartter syndrome (BS) type 1, a life-threatening salt-losing tubulopathy. We previously reported that this serious inherited renal disease is linked to the endoplasmic reticulum-associated degradation (ERAD) pathway. The purpose of this work is to characterize further the ERAD machinery of NKCC2. Here, we report the identification of ancient ubiquitous protein 1 (AUP1) as a novel interactor of NKCC2 ER-resident form in renal cells. AUP1 is also an interactor of the ER lectin OS9, a key player in the ERAD of NKCC2. Similar to OS9, AUP1 co-expression decreased the amount of total NKCC2 protein by enhancing the ER retention and associated protein degradation of the cotransporter. Blocking the ERAD pathway with the proteasome inhibitor MG132 or the α-mannosidase inhibitor kifunensine fully abolished the AUP1 effect on NKCC2. Importantly, AUP1 knock-down or inhibition by overexpressing its dominant negative form strikingly decreased NKCC2 polyubiquitination and increased the protein level of the cotransporter. Interestingly, AUP1 co-expression produced a more profound impact on NKCC2 folding mutants. Moreover, AUP1 also interacted with the related kidney cotransporter NCC and downregulated its expression, strongly indicating that AUP1 is a common regulator of sodium-dependent chloride cotransporters. In conclusion, our data reveal the presence of an AUP1-mediated pathway enhancing the polyubiquitination and ERAD of NKCC2. The characterization and selective regulation of specific ERAD constituents of NKCC2 and its pathogenic mutants could open new avenues in the therapeutic strategies for type 1 BS treatment. Full article
(This article belongs to the Special Issue Cellular and Molecular Basis in Chronic Kidney Disease)
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17 pages, 740 KiB  
Review
Protein Quality Control of NKCC2 in Bartter Syndrome and Blood Pressure Regulation
by Kamel Laghmani
Cells 2024, 13(10), 818; https://doi.org/10.3390/cells13100818 - 10 May 2024
Viewed by 783
Abstract
Mutations in NKCC2 generate antenatal Bartter syndrome type 1 (type 1 BS), a life-threatening salt-losing nephropathy characterized by arterial hypotension, as well as electrolyte abnormalities. In contrast to the genetic inactivation of NKCC2, inappropriate increased NKCC2 activity has been associated with salt-sensitive hypertension. [...] Read more.
Mutations in NKCC2 generate antenatal Bartter syndrome type 1 (type 1 BS), a life-threatening salt-losing nephropathy characterized by arterial hypotension, as well as electrolyte abnormalities. In contrast to the genetic inactivation of NKCC2, inappropriate increased NKCC2 activity has been associated with salt-sensitive hypertension. Given the importance of NKCC2 in salt-sensitive hypertension and the pathophysiology of prenatal BS, studying the molecular regulation of this Na-K-2Cl cotransporter has attracted great interest. Therefore, several studies have addressed various aspects of NKCC2 regulation, such as phosphorylation and post-Golgi trafficking. However, the regulation of this cotransporter at the pre-Golgi level remained unknown for years. Similar to several transmembrane proteins, export from the ER appears to be the rate-limiting step in the cotransporter’s maturation and trafficking to the plasma membrane. The most compelling evidence comes from patients with type 5 BS, the most severe form of prenatal BS, in whom NKCC2 is not detectable in the apical membrane of thick ascending limb (TAL) cells due to ER retention and ER-associated degradation (ERAD) mechanisms. In addition, type 1 BS is one of the diseases linked to ERAD pathways. In recent years, several molecular determinants of NKCC2 export from the ER and protein quality control have been identified. The aim of this review is therefore to summarize recent data regarding the protein quality control of NKCC2 and to discuss their potential implications in BS and blood pressure regulation. Full article
(This article belongs to the Special Issue Cellular and Molecular Basis in Chronic Kidney Disease)
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18 pages, 849 KiB  
Review
Unveiling Selected Influences on Chronic Kidney Disease Development and Progression
by Piotr Fularski, Witold Czarnik, Hanna Frankenstein, Magdalena Gąsior, Ewelina Młynarska, Jacek Rysz and Beata Franczyk
Cells 2024, 13(9), 751; https://doi.org/10.3390/cells13090751 - 26 Apr 2024
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Abstract
Currently, more and more people are suffering from chronic kidney disease (CKD). It is estimated that CKD affects over 10% of the population worldwide. This is a significant issue, as the kidneys largely contribute to maintaining homeostasis by, among other things, regulating blood [...] Read more.
Currently, more and more people are suffering from chronic kidney disease (CKD). It is estimated that CKD affects over 10% of the population worldwide. This is a significant issue, as the kidneys largely contribute to maintaining homeostasis by, among other things, regulating blood pressure, the pH of blood, and the water–electrolyte balance and by eliminating unnecessary metabolic waste products from blood. What is more, this disease does not show any specific symptoms at the beginning. The development of CKD is predisposed by certain conditions, such as diabetes mellitus or hypertension. However, these disorders are not the only factors promoting the onset and progression of CKD. The primary purpose of this review is to examine renin–angiotensin–aldosterone system (RAAS) activity, transforming growth factor-β1 (TGF-β1), vascular calcification (VC), uremic toxins, and hypertension in the context of their impact on the occurrence and the course of CKD. We firmly believe that a deeper comprehension of the cellular and molecular mechanisms underlying CKD can lead to an enhanced understanding of the disease. In the future, this may result in the development of medications targeting specific mechanisms involved in the decline of kidney function. Our paper unveils the selected processes responsible for the deterioration of renal filtration abilities. Full article
(This article belongs to the Special Issue Cellular and Molecular Basis in Chronic Kidney Disease)
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