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.

Background: In autosomal dominant polycystic kidney disease (ADPKD), cyst development and enlargement lead to end-stage kidney disease. Macrophage recruitment and interstitial inflammation have been shown to 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: In order 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 models 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, while TWEAK was significantly high in urine and cystic fluid from ADPKD patients. 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-MAPK signaling, decreased NF-κB pathway activation, slight reduction of fibrosis and apoptosis, and an indirect decrease of 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.

(1) Background: Polycystic liver disease (PLD) is a heterogeneous group of congenital disorders characterized by bile duct dilatation and cyst development derived from cholangiocytes. Nevertheless, the cystogenesis mechanism is currently unknown and the PLD treatment is limited to liver transplantation. Novel and efficient therapeutic approaches are th6us needed. In this context, the present work has a principal aim to find novel molecular pathways, as well as new therapeutic targets, involved in the hepatic cystogenesis process. (2) Methods: Quantitative proteomics based on SWATH–MS technology were performed comparing hepatic proteomes of Wild Type and mutant/polycystic livers in a polycystic kidney disease (PKD) murine model (Pkd1cond/cond;Tam-Cre−/+). (3) Results: We identified several proteins altered in abundance, with two-fold cut-off up-regulation or down-regulation and an adjusted p-value significantly related to hepatic cystogenesis. Then, we performed enrichment and a protein–protein analysis identifying a cluster focused on hepatic fibrinogens. Finally, we validated a selection of targets by RT-qPCR, Western blotting and immunohistochemistry, finding a high correlation with quantitative proteomics data and validating the fibrinogen complex. (4) Conclusions: This work identified a novel molecular pathway in cystic liver disease, highlighting the fibrinogen complex as a possible new therapeutic target for PLD.