Aberrant activation of the mammalian target of rapamycin (mTOR) pathway occurs in polycystic kidney disease (PKD). mTOR inhibitors, such as rapamycin, are highly effective in several rodent models of PKD, but these models result from mutations in genes other than Pkd1 and Pkd2, which are the primary genes responsible for human autosomal dominant PKD. To address this limitation, we tested the efficacy of rapamycin in a mouse model that results from conditional inactivation of Pkd1. Mosaic deletion of Pkd1 resulted in PKD and replicated characteristic features of human PKD including aberrant mTOR activation, epithelial proliferation and apoptosis, and progressive fibrosis. Treatment with rapamycin was highly effective: It reduced cyst growth, preserved renal function, inhibited epithelial cell proliferation, increased apoptosis of cyst-lining cells, and inhibited fibrosis. These data provide in vivo evidence that rapamycin is effective in a human-orthologous mouse model of PKD.
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"In 2005, a seminal paper treating Han:SPRD rats with rapamycin for 5 weeks demonstrated that cyst increase was reduced by >40% while the number of proliferating cell nuclear antigen positive cells was reduced. Soon afterwards these results were repeated with other mTOR inhibitors and in other rodent models of cystic kidney disease8788899091. Although there are parallels to renal cell cancer, where mTOR inhibitors have gained importance as a targeted therapeutic approach, there seem to be obvious differences in intracellular signalling mechanisms which lead to mTOR activation[92,93]. "
[Show abstract][Hide abstract] ABSTRACT: Renal epithelial function is the cornerstone of key excretory processes performed by our kidneys. Most of these tasks need
to be tightly controlled to keep our internal environment in balance. Recently, the mTOR signalling network emerged as a key
pathway controlling renal epithelial cells from the glomerular tuft along the entire nephron. Both mTOR complexes, mTORC1
and mTORC2, regulate such diverse processes as glomerular filtration and the fine tuning of tubular electrolyte balance. Most
importantly, dysregulation of mTOR signalling contributes to prevalent kidney diseases like diabetic nephropathy and cystic
kidney disease. The following review shall summarize our current knowledge of the renal epithelial mTOR signalling system
under physiological and pathophysiological conditions.
Full-text · Article · Feb 2014 · Nephrology Dialysis Transplantation
"Stained sections were visualized under bright field microscopy and twenty random fields of vision (FOV) in each experimental and control group were captured for quantification. Images were quantified using color deconvolution and Image-based Tool for Counting Nuclei (ITCN) plug-ins of ImageJ v1.46 software as per protocol described earlier ,,  and six mice in each group were used for quantification. Average number of Ki67 positive nuclei per animal is presented graphically and a representative image from each study group is presented in the results. "
[Show abstract][Hide abstract] ABSTRACT: Tissue consequences of radiation exposure are dependent on radiation quality and high linear energy transfer (high-LET) radiation, such as heavy ions in space is known to deposit higher energy in tissues and cause greater damage than low-LET γ radiation. While radiation exposure has been linked to intestinal pathologies, there are very few studies on long-term effects of radiation, fewer involved a therapeutically relevant γ radiation dose, and none explored persistent tissue metabolomic alterations after heavy ion space radiation exposure. Using a metabolomics approach, we report long-term metabolomic markers of radiation injury and perturbation of signaling pathways linked to metabolic alterations in mice after heavy ion or γ radiation exposure. Intestinal tissues (C57BL/6J, female, 6 to 8 wks) were analyzed using ultra performance liquid chromatography coupled with electrospray quadrupole time-of-flight mass spectrometry (UPLC-QToF-MS) two months after 2 Gy γ radiation and results were compared to an equitoxic (56)Fe (1.6 Gy) radiation dose. The biological relevance of the metabolites was determined using Ingenuity Pathway Analysis, immunoblots, and immunohistochemistry. Metabolic profile analysis showed radiation-type-dependent spatial separation of the groups. Decreased adenine and guanosine and increased inosine and uridine suggested perturbed nucleotide metabolism. While both the radiation types affected amino acid metabolism, the (56)Fe radiation preferentially altered dipeptide metabolism. Furthermore, (56)Fe radiation caused upregulation of 'prostanoid biosynthesis' and 'eicosanoid signaling', which are interlinked events related to cellular inflammation and have implications for nutrient absorption and inflammatory bowel disease during space missions and after radiotherapy. In conclusion, our data showed for the first time that metabolomics can not only be used to distinguish between heavy ion and γ radiation exposures, but also as a radiation-risk assessment tool for intestinal pathologies through identification of biomarkers persisting long after exposure.
"A low frequency of renal Pkd1 gene inactivation and only a few renal cysts and more frequent hepatic cysts is reported from the conditional deletion of Pkd1 in MMTV-Cre mice , whereas the broadly expressed tamoxifen-Cre inducible inactivation of the Pkd1 gene in mice resulted in massive cystic transformation of renal tissue . The selective deletion of Pkd1 in kidney by using Ksp-Cre, or more broadly Nestin-Cre, also leads to the formation of polycystic kidneys resembling human ADPKD , . "
[Show abstract][Hide abstract] ABSTRACT: Conditional deletion of Pkd1 in osteoblasts using either Osteocalcin(Oc)-Cre or Dmp1-Cre results in defective osteoblast-mediated postnatal bone formation and osteopenia. Pkd1 is also expressed in undifferentiated mesenchyme that gives rise to the osteoblast lineage. To examine the effects of Pkd1 on prenatal osteoblast development, we crossed Pkd1(flox/flox) and Col1a1(3.6)-Cre mice, which has been used to achieve selective inactivation of Pkd1 earlier in the osteoblast lineage. Control Pkd1(flox/flox) and Pkd1(flox/+), heterozygous Col1a1(3.6)-Cre;Pkd1(flox/+) and Pkd1(flox/null), and homozygous Col1a1(3.6)-Cre;Pkd1(flox/flox) and Col1a1(3.6)-Cre;Pkd1(flox/null) mice were analyzed at ages ranging from E14.5 to 8-weeks-old. Newborn Col1a1(3.6)-Cre;Pkd1(flox/null) mice exhibited defective skeletogenesis in association with a greater reduction in Pkd1 expression in bone. Conditional Col1a1(3.6)-Cre;Pkd1(flox/+) and Col1a1(3.6)-Cre;Pkd1(flox/flox) mice displayed a gene dose-dependent decrease in bone formation and increase in marrow fat at 6 weeks of age. Bone marrow stromal cell and primary osteoblast cultures from homozygous Col1a1(3.6)-Cre;Pkd1(flox/flox) mice showed increased proliferation, impaired osteoblast development and enhanced adipogenesis ex vivo. Unexpectedly, we found evidence for Col1a1(3.6)-Cre mediated deletion of Pkd1 in extraskeletal tissues in Col1a1(3.6)-Cre;Pkd1(flox/flox) mice. Deletion of Pkd1 in mesenchymal precursors resulted in pancreatic and renal, but not hepatic, cyst formation. The non-lethality of Col1a1(3.6)-Cre;Pkd1(flox/flox) mice establishes a new model to study abnormalities in bone development and cyst formation in pancreas and kidney caused by Pkd1 gene inactivation.