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1543 KiB

Open AccessArticle

Uremic Toxins Induce ET-1 Release by Human Proximal Tubule Cells, which Regulates Organic Cation Uptake Time-Dependently

by Carolien M. S. Schophuizen, Joost G. J. Hoenderop, Rosalinde Masereeuw and Lambert P. van den Heuvel

Cells 2015, 4(3), 234-252; https://doi.org/10.3390/cells4030234 - 26 Jun 2015

Cited by 6 | Viewed by 6077

Abstract

In renal failure, the systemic accumulation of uremic waste products is strongly associated with the development of a chronic inflammatory state. Here, the effect of cationic uremic toxins on the release of inflammatory cytokines and endothelin-1 (ET-1) was investigated in conditionally immortalized proximal [...] Read more.

In renal failure, the systemic accumulation of uremic waste products is strongly associated with the development of a chronic inflammatory state. Here, the effect of cationic uremic toxins on the release of inflammatory cytokines and endothelin-1 (ET-1) was investigated in conditionally immortalized proximal tubule epithelial cells (ciPTEC). Additionally, we examined the effects of ET-1 on the cellular uptake mediated by organic cation transporters (OCTs). Exposure of ciPTEC to cationic uremic toxins initiated production of the inflammatory cytokines IL-6 (117 ± 3%, p < 0.001), IL-8 (122 ± 3%, p < 0.001), and ET-1 (134 ± 5%, p < 0.001). This was accompanied by a down-regulation of OCT mediated 4-(4-(dimethylamino)styryl)-N-methylpyridinium-iodide (ASP⁺) uptake in ciPTEC at 30 min (23 ± 4%, p < 0.001), which restored within 60 min of incubation. Exposure to ET-1 for 24 h increased the ASP⁺ uptake significantly (20 ± 5%, p < 0.001). These effects could be blocked by BQ-788, indicating activation of an ET-B-receptor-mediated signaling pathway. Downstream the receptor, iNOS inhibition by (N(G)‐monomethyl‐l‐arginine) l-NMMA acetate or aminoguanidine, as well as protein kinase C activation, ameliorated the short-term effects. These results indicate that uremia results in the release of cytokines and ET-1 from human proximal tubule cells, in vitro. Furthermore, ET-1 exposure was found to regulate proximal tubular OCT transport activity in a differential, time-dependent, fashion. Full article

(This article belongs to the Special Issue The Kidney: Development, Disease and Regeneration)

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Review

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875 KiB

Open AccessReview

The Role of G-Protein-Coupled Receptor Proteolysis Site Cleavage of Polycystin-1 in Renal Physiology and Polycystic Kidney Disease

by Marie Trudel, Qin Yao and Feng Qian

Cells 2016, 5(1), 3; https://doi.org/10.3390/cells5010003 - 21 Jan 2016

Cited by 33 | Viewed by 8552

Abstract

Polycystin-1 (PC1) plays an essential role in renal tubular morphogenesis, and PC1 dysfunction causes human autosomal dominant polycystic kidney disease. A fundamental characteristic of PC1 is post-translational modification via cleavage at the juxtamembrane GPCR proteolysis site (GPS) motif that is part of the [...] Read more.

Polycystin-1 (PC1) plays an essential role in renal tubular morphogenesis, and PC1 dysfunction causes human autosomal dominant polycystic kidney disease. A fundamental characteristic of PC1 is post-translational modification via cleavage at the juxtamembrane GPCR proteolysis site (GPS) motif that is part of the larger GAIN domain. Given the considerable biochemical complexity of PC1 molecules generated in vivo by this process, GPS cleavage has several profound implications on the intracellular trafficking and localization in association with their particular function. The critical nature of GPS cleavage is further emphasized by the increasing numbers of PKD1 mutations that significantly affect this cleavage process. The GAIN domain with the GPS motif therefore represents the key structural element with fundamental importance for PC1 and might be polycystic kidney disease’s (PKD) Achilles’ heel in a large spectrum of PKD1 missense mutations. We highlight the central roles of PC1 cleavage for the regulation of its biogenesis, intracellular trafficking and function, as well as its significance in polycystic kidney disease. Full article

(This article belongs to the Special Issue The Kidney: Development, Disease and Regeneration)

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1471 KiB

Open AccessReview

Role of the Polycystins in Cell Migration, Polarity, and Tissue Morphogenesis

by Elisa Agnese Nigro, Maddalena Castelli and Alessandra Boletta

Cells 2015, 4(4), 687-705; https://doi.org/10.3390/cells4040687 - 30 Oct 2015

Cited by 21 | Viewed by 9772

Abstract

Cystic kidney diseases (CKD) is a class of disorders characterized by ciliary dysfunction and, therefore, belonging to the ciliopathies. The prototype CKD is autosomal dominant polycystic kidney disease (ADPKD), whose mutated genes encode for two membrane-bound proteins, polycystin-1 (PC-1) and polycystin-2 (PC-2), of [...] Read more.

Cystic kidney diseases (CKD) is a class of disorders characterized by ciliary dysfunction and, therefore, belonging to the ciliopathies. The prototype CKD is autosomal dominant polycystic kidney disease (ADPKD), whose mutated genes encode for two membrane-bound proteins, polycystin-1 (PC-1) and polycystin-2 (PC-2), of unknown function. Recent studies on CKD-associated genes identified new mechanisms of morphogenesis that are central for establishment and maintenance of proper renal tubular diameter. During embryonic development in the mouse and lower vertebrates a convergent-extension (CE)-like mechanism based on planar cell polarity (PCP) and cellular intercalation is involved in “sculpting” the tubules into a narrow and elongated shape. Once the appropriate diameter is established, further elongation occurs through oriented cell division (OCD). The polycystins (PCs) regulate some of these essential processes. In this review we summarize recent work on the role of PCs in regulating cell migration, the cytoskeleton, and front-rear polarity. These important properties are essential for proper morphogenesis of the renal tubules and the lymphatic vessels. We highlight here several open questions and controversies. Finally, we try to outline some of the next steps required to study these processes and their relevance in physiological and pathological conditions. Full article

(This article belongs to the Special Issue The Kidney: Development, Disease and Regeneration)

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1384 KiB

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Epithelial-to-Mesenchymal Transition in Diabetic Nephropathy: Fact or Fiction?

by Ivonne Loeffler and Gunter Wolf

Cells 2015, 4(4), 631-652; https://doi.org/10.3390/cells4040631 - 9 Oct 2015

Cited by 221 | Viewed by 12461

Abstract

The pathophysiology of diabetic nephropathy (DN), one of the most serious complications in diabetic patients and the leading cause of end-stage renal disease worldwide, is complex and not fully elucidated. A typical hallmark of DN is the excessive deposition of extracellular matrix (ECM) [...] Read more.

The pathophysiology of diabetic nephropathy (DN), one of the most serious complications in diabetic patients and the leading cause of end-stage renal disease worldwide, is complex and not fully elucidated. A typical hallmark of DN is the excessive deposition of extracellular matrix (ECM) proteins in the glomerulus and in the renal tubulointerstitium, eventually leading to glomerulosclerosis and interstitial fibrosis. Although it is obvious that myofibroblasts play a major role in the synthesis and secretion of ECM, the origin of myofibroblasts in DN remains the subject of controversial debates. A number of studies have focused on epithelial-to-mesenchymal transition (EMT) as one source of matrix-generating fibroblasts in the diseased kidney. EMT is characterized by the acquisition of mesenchymal properties by epithelial cells, preferentially proximal tubular cells and podocytes. In this review we comprehensively review the literature and discuss arguments both for and against a function of EMT in renal fibrosis in DN. While the precise extent of the contribution to nephrotic fibrosis is certainly arduous to quantify, the picture that emerges from this extensive body of literature suggests EMT as a major source of myofibroblasts in DN. Full article

(This article belongs to the Special Issue The Kidney: Development, Disease and Regeneration)

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673 KiB

Open AccessReview

Albumin and Furosemide Combination for Management of Edema in Nephrotic Syndrome: A Review of Clinical Studies

by Margaret Duffy, Shashank Jain, Nicholas Harrell, Neil Kothari and Alluru S. Reddi

Cells 2015, 4(4), 622-630; https://doi.org/10.3390/cells4040622 - 7 Oct 2015

Cited by 39 | Viewed by 20395

Abstract

The treatment of edema in patients with nephrotic syndrome is generally managed by dietary sodium restriction and loop diuretics. However, edema does not improve in some patients despite adequate sodium restriction and maximal dose of diuretics. In such patients, combination of albumin and [...] Read more.

The treatment of edema in patients with nephrotic syndrome is generally managed by dietary sodium restriction and loop diuretics. However, edema does not improve in some patients despite adequate sodium restriction and maximal dose of diuretics. In such patients, combination of albumin and a loop diuretic may improve edema by diuresis and natriuresis. The response to this combination of albumin and a diuretic has not been observed in all studies. The purpose of this review is to discuss the physiology of diuresis and natriuresis of this combination therapy, and provide a brief summary of various studies that have used albumin and a loop diuretic to improve diuretic-resistant edema. Also, the review suggests various reasons for not observing similar results by various investigators. Full article

(This article belongs to the Special Issue The Kidney: Development, Disease and Regeneration)

3575 KiB

Open AccessReview

Nephron Patterning: Lessons from Xenopus, Zebrafish, and Mouse Studies

by Audrey Desgrange and Silvia Cereghini

Cells 2015, 4(3), 483-499; https://doi.org/10.3390/cells4030483 - 11 Sep 2015

Cited by 68 | Viewed by 11682

Abstract

The nephron is the basic structural and functional unit of the vertebrate kidney. To ensure kidney functions, the nephrons possess a highly segmental organization where each segment is specialized for the secretion and reabsorption of particular solutes. During embryogenesis, nephron progenitors undergo a [...] Read more.

The nephron is the basic structural and functional unit of the vertebrate kidney. To ensure kidney functions, the nephrons possess a highly segmental organization where each segment is specialized for the secretion and reabsorption of particular solutes. During embryogenesis, nephron progenitors undergo a mesenchymal-to-epithelial transition (MET) and acquire different segment-specific cell fates along the proximo-distal axis of the nephron. Even if the morphological changes occurring during nephrogenesis are characterized, the regulatory networks driving nephron segmentation are still poorly understood. Interestingly, several studies have shown that the pronephric nephrons in Xenopus and zebrafish are segmented in a similar fashion as the mouse metanephric nephrons. Here we review functional and molecular aspects of nephron segmentation with a particular interest on the signaling molecules and transcription factors recently implicated in kidney development in these three different vertebrate model organisms. A complete understanding of the mechanisms underlying nephrogenesis in different model organisms will provide novel insights on the etiology of several human renal diseases. Full article

(This article belongs to the Special Issue The Kidney: Development, Disease and Regeneration)

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1554 KiB

Open AccessReview

Recent Advances in Elucidating the Genetic Mechanisms of Nephrogenesis Using Zebrafish

by Christina N. Cheng, Valerie A. Verdun and Rebecca A. Wingert

Cells 2015, 4(2), 218-233; https://doi.org/10.3390/cells4020218 - 27 May 2015

Cited by 16 | Viewed by 6900

Abstract

The kidney is comprised of working units known as nephrons, which are epithelial tubules that contain a series of specialized cell types organized into a precise pattern of functionally distinct segment domains. There is a limited understanding of the genetic mechanisms that establish [...] Read more.

The kidney is comprised of working units known as nephrons, which are epithelial tubules that contain a series of specialized cell types organized into a precise pattern of functionally distinct segment domains. There is a limited understanding of the genetic mechanisms that establish these discrete nephron cell types during renal development. The zebrafish embryonic kidney serves as a simplified yet conserved vertebrate model to delineate how nephron segments are patterned from renal progenitors. Here, we provide a concise review of recent advances in this emerging field, and discuss how continued research using zebrafish genetics can be applied to gain insights about nephrogenesis. Full article

(This article belongs to the Special Issue The Kidney: Development, Disease and Regeneration)

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1282 KiB

Open AccessReview

Signaling during Kidney Development

by Mirja Krause, Aleksandra Rak-Raszewska, Ilkka Pietilä, Susan E. Quaggin and Seppo Vainio

Cells 2015, 4(2), 112-132; https://doi.org/10.3390/cells4020112 - 10 Apr 2015

Cited by 49 | Viewed by 13186

Abstract

The kidney plays an essential role during excretion of metabolic waste products, maintenance of key homeostasis components such as ion concentrations and hormone levels. It influences the blood pressure, composition and volume. The kidney tubule system is composed of two distinct cell populations: [...] Read more.

The kidney plays an essential role during excretion of metabolic waste products, maintenance of key homeostasis components such as ion concentrations and hormone levels. It influences the blood pressure, composition and volume. The kidney tubule system is composed of two distinct cell populations: the nephrons forming the filtering units and the collecting duct system derived from the ureteric bud. Nephrons are composed of glomeruli that filter the blood to the Bowman’s capsule and tubular structures that reabsorb and concentrate primary urine. The collecting duct is a Wolffian duct-derived epithelial tube that concentrates and collects urine and transfers it via the renal pelvis into the bladder. The mammalian kidney function depends on the coordinated development of specific cell types within a precise architectural framework. Due to the availability of modern analysis techniques, the kidney has become a model organ defining the paradigm to study organogenesis. As kidney diseases are a problem worldwide, the understanding of mammalian kidney cells is of crucial importance to develop diagnostic tools and novel therapies. This review focuses on how the pattern of renal development is generated, how the inductive signals are regulated and what are their effects on proliferation, differentiation and morphogenesis. Full article

(This article belongs to the Special Issue The Kidney: Development, Disease and Regeneration)

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