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Rodent Autosomal Dominant Polycystic Kidney Disease Models
Published in Jinghua Hu, Yong Yu, Polycystic Kidney Disease, 2019
Sara J. Holditch, Raphael A. Nemenoff, Katharina Hopp
In order to better understand the pathomechanism underlying PC1/PC2 loss in adult mice, and to have relevant models for translational studies, spatiotemporal conditional and inducible knockout mice of Pkd1/Pkd2 have been generated. Initially, researchers focused on kidney-specific gene knockouts using the conditional Cre-loxP system outlined in Section 10.2. In these cases, Pkd1flox/flox or Pkd2flox/flox mice are crossed with mice transgenic for the Cre-recombinase gene cloned into a promoter system of a second gene typically expressed exclusively within the kidney. Hence, Cre recombinase is only expressed and active, and Pkd1/Pkd2 disrupted (i.e., knocked-out) wherever the endogenous gene of the given promoter is being actively transcribed (e.g., the kidney). This approach has been utilized implementing many different promoter systems as outlined in Table 10.1. Of note, the resulting PKD phenotype is dependent upon the time during embryonic development the promoter system becomes active, and in which kidney segment it is being transcribed. For example, the promoter of gamma-glutamyl transferase-1, Ggt1, starts being transcribed at E7, and expression is limited to the developing cortical tubular epithelium. Ggt1-Cre;Pkd1tm3.1Jzh(Ggt1-Cre;Pkd1flox/flox del2–6)95 mice present with rapid formation of proximal and distal nephron cysts, with a 28-day postnatal (PN) survival. Similarly, kidney-specific cadherin 16 (Cdh16 or Ksp) promoted Cre recombinase in Cdh16-Cre;Pkd1tm2.1Som (Ksp-Cre;Pkd1flox/flox del2–4)96 mice, results in exon excision at E11.5. Ksp-Cre;Pkd1flox/flox del2–4 mice have a 21-day PN survival, and cyst formation in the thick ascending limb through the collecting duct. While conditional models such as these survive embryonic development, the vast majority of kidney-specific conditional ADPKD models present with rapidly progressive disease resulting in early postnatal lethality. Unfortunately, the shortened life span of conditional models does not support preclinical trial development or mechanistic studies of adult disease.
Encapsulation of S-nitrosoglutathione: a transcriptomic validation
Published in Drug Development and Industrial Pharmacy, 2019
Ramia Safar, Rémi Houlgatte, Alain Le Faou, Carole Ronzani, Wen Wu, Luc Ferrari, Hélène Dubois-Pot-Schneider, Bertrand H. Rihn, Olivier Joubert
“GSNO6” exposure induces the modification of the expression of more genes than “GSNO1.4” indicating a dose dependent gene activation among which two up-regulated genes that are involved in GSNO catabolism, gamma glutamyl transpeptidase (GGT1), a transmembrane protein that converts the extracellular GSNO into intracellular S-nitrosocysteinylglycine [33], and thioredoxin reductase-1 (TXNRD1) that catalyzes the liberation of NO• [31]. Both genes are involved in the defense against oxidative stress, GGT1 being a part of the glutathione regulation system [34–36]. Besides, the iNOS signaling pathway is activated, although iNOS expression is not altered in both “GSNO1.4” and “GSNO6” conditions. Moreover, two genes involved in iNOS signaling activation are up-regulated: interleukin 1 receptor associated kinase 1 (IRAK1) and myeloid differentiation primary response 88 (MYD88), both functioning downstream of Toll-like receptor activation. Noteworthy that iNOs signaling pathway was not activated in presence of GNP, whatever the exposure conditions. The progressive release of GSNO, which has been already observed, may be, like stated above, the reason of this observation [16].
Hidden age-related hearing loss and hearing disorders: current knowledge and future directions
Published in Hearing, Balance and Communication, 2018
Richard Salvi, Dalian Ding, Haiyan Jiang, Guang-Di Chen, Antonio Greco, Senthilvelan Manohar, Wei Sun, Massimo Ralli
A major theory of aging involves oxidative stress from reactive oxygen species (ROS) [56,57]. The importance of ROS in ARHL in humans is ambiguous [58–60]. Inconsistencies in the human literature could be due to genetic diversity in the human population and/or environmental factors. Studies in mouse models in which oxidative stress can be genetically altered provide strong support for the oxidative stress in ARHL. Glutathione (GSH), which is one of the most important antioxidants for protecting cells, is heavily expressed in the cochlea. Intracellular GSH is resynthesized through the gamma-glutamyl cycle. The Ggt1gene codes for gamma-glutamyl transferase 1 (GGT1); GGT1 transfers the glutamyl moiety of GSH to an acceptor molecule facilitating its transport into the cell [61]. Loss of GGT1 depletes intracellular GSH resulting in increased oxidative stress. We recently found that dwg/dwg mice with a spontaneous loss of function mutation of the Ggt1 gene develop an unusual form of progressive ARHL that involves the selective loss of IHC in the apical half of the cochlea [62]. As shown by cochleograms in Figure 8(A), the IHC were intact up to 3 months of age, but by 6 months of age large IHC lesions were present in the low-frequency apical half of the cochlea and the lesions increased at 9 months of age. Importantly, the OHC remained intact in dwg/dwg mice and there did not appear to be any loss of auditory nerve fibres. No lesions were observed in the heterozygous dwg mice suggesting that 50% of the GGT1 protein was sufficient to prevent oxidative stress and preserve the integrity of the IHC. N-acetyl cysteine (NAC) promotes the synthesis of glutathione and has been found to ameliorate several forms of hearing loss. Since NAC promotes the synthesis of glutathione and protects against hearing loss [63–67], we added NAC to the drinking water of dwg/dwg mice from 3 weeks to 6 months of age. NAC treatment completely prevented the age-related loss of IHC (Figure 8(B)). When NAC treatment was discontinued from 6 to 9 months, the IHC lesion reappeared confirming the importance of NAC supplementation in preventing oxidative stress by replenishing the intracellular stores of GSH.