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A Molecular Perspective on the Genetics of Kidney Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: 15 July 2024 | Viewed by 1772

Special Issue Editor


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Guest Editor
NOVA Medical School—Faculdade de Ciências Médicas, Universidade de Lisboa, Lisboa, Portugal
Interests: inherited kidney diseases; disorders of transepithelial transport; kidney inflammation; dysmetabolism; phenotype evaluation (clinical); human molecular genetics (sequencing and/or genotyping)

Special Issue Information

Dear Colleagues,

Unravelling the genetic and genomic basis of kidney diseases has not only fostered our ability to personalize kidney medicine, with a particular focus in the genetic diagnosis of inherited kidney disorders, but has also set up the groundwork for a molecular characterization of the pathogenesis of both rare inherited phenotypes as well common diseases and traits in which heritability plays a role. With the current call, the Editorial Board aims to collect examples of how research in genetics and genomics has leveraged precision kidney care. We hope that the authors, with their unique expertise in the field, will embrace the challenge and contribute to the current issue’s success.

Dr. Joaquim Calado
Guest Editor

Manuscript Submission Information

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Keywords

  • kidney
  • genetics
  • solute transport
  • genomics
  • inflammation
  • dysmetabolism

Published Papers (3 papers)

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Research

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27 pages, 5003 KiB  
Article
Multi-Omic Analysis Reveals Genetic Determinants and Therapeutic Targets of Chronic Kidney Disease and Kidney Function
by Yao-Qi Lu and Yirong Wang
Int. J. Mol. Sci. 2024, 25(11), 6033; https://doi.org/10.3390/ijms25116033 - 30 May 2024
Viewed by 381
Abstract
Chronic kidney disease (CKD) presents a significant global health challenge, characterized by complex pathophysiology. This study utilized a multi-omic approach, integrating genomic data from the CKDGen consortium alongside transcriptomic, metabolomic, and proteomic data to elucidate the genetic underpinnings and identify therapeutic targets for [...] Read more.
Chronic kidney disease (CKD) presents a significant global health challenge, characterized by complex pathophysiology. This study utilized a multi-omic approach, integrating genomic data from the CKDGen consortium alongside transcriptomic, metabolomic, and proteomic data to elucidate the genetic underpinnings and identify therapeutic targets for CKD and kidney function. We employed a range of analytical methods including cross-tissue transcriptome-wide association studies (TWASs), Mendelian randomization (MR), summary-based MR (SMR), and molecular docking. These analyses collectively identified 146 cross-tissue genetic associations with CKD and kidney function. Key Golgi apparatus-related genes (GARGs) and 41 potential drug targets were highlighted, with MAP3K11 emerging as a significant gene from the TWAS and MR data, underscoring its potential as a therapeutic target. Capsaicin displayed promising drug–target interactions in molecular docking analyses. Additionally, metabolome- and proteome-wide MR (PWMR) analyses revealed 33 unique metabolites and critical inflammatory proteins such as FGF5 that are significantly linked to and colocalized with CKD and kidney function. These insights deepen our understanding of CKD pathogenesis and highlight novel targets for treatment and prevention. Full article
(This article belongs to the Special Issue A Molecular Perspective on the Genetics of Kidney Diseases)
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14 pages, 9051 KiB  
Article
Carbonic Anhydrase 2 Deletion Delays the Growth of Kidney Cysts Whereas Foxi1 Deletion Completely Abrogates Cystogenesis in TSC
by Sharon Barone, Kamyar Zahedi, Marybeth Brooks and Manoocher Soleimani
Int. J. Mol. Sci. 2024, 25(9), 4772; https://doi.org/10.3390/ijms25094772 - 27 Apr 2024
Viewed by 783
Abstract
Tuberous sclerosis complex (TSC) presents with renal cysts and benign tumors, which eventually lead to kidney failure. The factors promoting kidney cyst formation in TSC are poorly understood. Inactivation of carbonic anhydrase 2 (Car2) significantly reduced, whereas, deletion of Foxi1 completely abrogated [...] Read more.
Tuberous sclerosis complex (TSC) presents with renal cysts and benign tumors, which eventually lead to kidney failure. The factors promoting kidney cyst formation in TSC are poorly understood. Inactivation of carbonic anhydrase 2 (Car2) significantly reduced, whereas, deletion of Foxi1 completely abrogated the cyst burden in Tsc1 KO mice. In these studies, we contrasted the ontogeny of cyst burden in Tsc1/Car2 dKO mice vs. Tsc1/Foxi1 dKO mice. Compared to Tsc1 KO, the Tsc1/Car2 dKO mice showed few small cysts at 47 days of age. However, by 110 days, the kidneys showed frequent and large cysts with overwhelming numbers of A-intercalated cells in their linings. The magnitude of cyst burden in Tsc1/Car2 dKO mice correlated with the expression levels of Foxi1 and was proportional to mTORC1 activation. This is in stark contrast to Tsc1/Foxi1 dKO mice, which showed a remarkable absence of kidney cysts at both 47 and 110 days of age. RNA-seq data pointed to profound upregulation of Foxi1 and kidney-collecting duct-specific H+-ATPase subunits in 110-day-old Tsc1/Car2 dKO mice. We conclude that Car2 inactivation temporarily decreases the kidney cyst burden in Tsc1 KO mice but the cysts increase with advancing age, along with enhanced Foxi1 expression. Full article
(This article belongs to the Special Issue A Molecular Perspective on the Genetics of Kidney Diseases)
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Review

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19 pages, 1509 KiB  
Review
The Role of the PAX Genes in Renal Cell Carcinoma
by Lei Li, Sultana Mehbuba Hossain and Michael R. Eccles
Int. J. Mol. Sci. 2024, 25(12), 6730; https://doi.org/10.3390/ijms25126730 - 19 Jun 2024
Viewed by 287
Abstract
Renal cell carcinoma (RCC) is a significant oncological challenge due to its heterogeneous nature and limited treatment options. The PAX developmental gene family encodes nine highly conserved transcription factors that play crucial roles in embryonic development and organogenesis, which have been implicated in [...] Read more.
Renal cell carcinoma (RCC) is a significant oncological challenge due to its heterogeneous nature and limited treatment options. The PAX developmental gene family encodes nine highly conserved transcription factors that play crucial roles in embryonic development and organogenesis, which have been implicated in the occurrence and development of RCC. This review explores the molecular landscape of RCC, with a specific focus on the role of the PAX gene family in RCC tumorigenesis and disease progression. Of the various RCC subtypes, clear cell renal cell carcinoma (ccRCC) is the most prevalent, characterized by the loss of the von Hippel–Lindau (VHL) tumor suppressor gene. Here, we review the published literature on the expression patterns and functional implications of PAX genes, particularly PAX2 and PAX8, in the three most common RCC subtypes, including ccRCC, papillary RCC (PRCC), and chromophobe RCC (ChRCC). Further, we review the interactions and potential biological mechanisms involving PAX genes and VHL loss in driving the pathogenesis of RCC, including the key signaling pathways mediated by VHL in ccRCC and associated mechanisms implicating PAX. Lastly, concurrent with our update regarding PAX gene research in RCC, we review and comment on the targeting of PAX towards the development of novel RCC therapies. Full article
(This article belongs to the Special Issue A Molecular Perspective on the Genetics of Kidney Diseases)
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