Gitelman and Bartter syndromes are rare inherited diseases that belong to the category of renal tubulopathies. The genes associated with these pathologies encode electrolyte transport proteins located in the nephron, particularly in the Distal Convoluted Tubule and Ascending Loop of Henle. Therefore, both syndromes are characterized by alterations in the secretion and reabsorption processes that occur in these regions. Patients suffer from deficiencies in the concentration of electrolytes in the blood and urine, which leads to different systemic consequences related to these salt-wasting processes. The main clinical features of both syndromes are hypokalemia, hypochloremia, metabolic alkalosis, hyperreninemia and hyperaldosteronism. Despite having a different molecular etiology, Gitelman and Bartter syndromes share a relevant number of clinical symptoms, and they have similar therapeutic approaches. The main basis of their treatment consists of electrolytes supplements accompanied by dietary changes. Specifically for Bartter syndrome, the use of non-steroidal anti-inflammatory drugs is also strongly supported. This review aims to address the latest diagnostic challenges and therapeutic approaches, as well as relevant recent research on the biology of the proteins involved in disease. Finally, we highlight several objectives to continue advancing in the characterization of both etiologies.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic disorders worldwide. In recent decades, the field has undergone a revolution, starting with the identification of causal ADPKD genes, including PKD1, PKD2, and the recently identified GANAB. In addition, advances defining the genetic mechanisms, protein localization and function, and the identification of numerous pathways involved in the disease process, have contributed to a better understanding of this illness. Together, this has led to a better prognosis, diagnosis, and treatment in clinical practice. In this mini review, we summarize and discuss new insights about the molecular mechanisms underlying ADPKD, including its genetics, protein function, and cellular pathways.

Significance Statement: In autosomal dominant polycystic kidney disease (ADPKD), interstitial inflammation promotes cyst progression. TWEAK is a TNF superfamily cytokine that regulates inflammatory responses, and its receptor, Fn14, is expressed in nephron epithelium. This paper describes TWEAK’s role in ADPKD and its potential as a therapeutic target. The Fn14/TWEAK axis is upregulated in human and mouse polycystic kidneys, and TWEAK administration in mice accelerates cyst progression, whereas anti-TWEAK treatment slows cyst growth, improving kidney function and survival. Anti-TWEAK antibodies restore several ADPKD-related pathways, such as proliferation and NF-κB; slightly reduces fibrosis and apoptosis; and indirectly decreases macrophage recruitment. These findings identify the TWEAK signaling pathway as a new disease mechanism in ADPKD and a new possible therapeutic approach. Background: In autosomal dominant polycystic kidney disease (ADPKD), cyst development and enlargement lead to ESKD. Macrophage recruitment and interstitial inflammation promote cyst growth. TWEAK is a TNF superfamily (TNFSF) cytokine that regulates inflammatory responses, cell proliferation, and cell death, and its receptor Fn14 (TNFRSF12a) is expressed in macrophage and nephron epithelia. Methods: To evaluate the role of the TWEAK signaling pathway in cystic disease, we evaluated Fn14 expression in human and in an orthologous murine model of ADPKD. We also explored the cystic response to TWEAK signaling pathway activation and inhibition by peritoneal injection. Results: Meta-analysis of published animal-model data of cystic disease reveals mRNA upregulation of several components of the TWEAK signaling pathway. We also observed that TWEAK and Fn14 were overexpressed in mouse ADPKD kidney cysts, and TWEAK was significantly high in urine and cystic fluid from patients with ADPKD. TWEAK administration induced cystogenesis and increased cystic growth, worsening the phenotype in a murine ADPKD model. Anti-TWEAK antibodies significantly slowed the progression of ADPKD, preserved renal function, and improved survival. Furthermore, the anti-TWEAK cystogenesis reduction is related to decreased cell proliferation–related MAPK signaling, decreased NF-κB pathway activation, a slight reduction of fibrosis and apoptosis, and an indirect decrease in macrophage recruitment. Conclusions: This study identifies the TWEAK signaling pathway as a new disease mechanism involved in cystogenesis and cystic growth and may lead to a new therapeutic approach in ADPKD.

Autosomal recessive polycystic kidney disease (ARPKD) is a rare disorder and one of the most severe forms of polycystic kidney disease, leading to end-stage renal disease (ESRD) in childhood. PKHD1 is the gene that is responsible for the vast majority of ARPKD. However, some cases have been related to a new gene that was recently identified (DZIP1L gene), as well as several ciliary genes that can mimic a ARPKD-like phenotypic spectrum. In addition, a number of molecular pathways involved in the ARPKD pathogenesis and progression were elucidated using cellular and animal models. However, the function of the ARPKD proteins and the molecular mechanism of the disease currently remain incompletely understood. Here, we review the clinics, treatment, genetics, and molecular basis of ARPKD, highlighting the most recent findings in the field.

The HNF1B gene, located on chromosome 17q12, encodes a transcription factor essential for the development of several organs. It regulates the expression of multiple genes in renal, pancreatic, hepatic, neurological, and genitourinary tissues during prenatal and postnatal development, influencing processes such as nephrogenesis, cellular polarity, tight junction formation, cilia development, ion transport in the renal tubule, and renal metabolism. Mutations that alter the function of Hnf1b deregulate those processes, leading to various pathologies characterized by both renal and extrarenal manifestations. The main renal diseases that develop are polycystic kidney disease, hypoplastic or dysplastic kidneys, structural abnormalities, Congenital Anomalies of the Kidney and Urinary Tract (CAKUT), and electrolyte imbalances such as hyperuricemia and hypomagnesemia. Extrarenal manifestations include Maturity-Onset Diabetes of the Young (MODY), hypertransaminasemia, genital and urinary tract malformations, Autism Spectrum Disorder (ASD), and other neurodevelopmental disorders. Patients with HNF1B alterations typically carry either punctual mutations or a monoallelic microdeletion in the 17q12 region. Future research on the molecular mechanisms and genotype–phenotype correlations in HNF1B-related conditions will enhance our understanding, leading to improved clinical management, genetic counseling, monitoring, and patient care.

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations of PKD1 and PKD2. Murine gene targeting studies have shown that these genes play an essential role in development, with homozygous inactivation resulting in embryonic lethality. Recently, Pkd1^−/− lethality has been linked to placental insufficiency. In this study, the placenta was used as a model to identify factors involved in these developmental abnormalities. Microarray analysis of Pkd1^−/− placentae showed upregulation of a set of apolipoprotein-related genes. These changes were validated and were found to be associated with increased quantities of apolipoproteins in the amniotic fluid. Increased apolipoprotein gene expression was also observed in Pkd2^−/−placentae and in cystic kidneys of Pkd1^cond/−; Meox2^cre/+ mice. Using chromatin immunoprecipitation assays, we determined that the activity of HNF-4α, a major regulator of apolipoprotein gene expression, was also increased in these organs. These findings suggest a potential role for dysregulation of nuclear hormone receptors in the pathogenesis of ADPKD.