New insight into the role of extracellular vesicles in kidney disease

Extracellular vesicles (EVs) are released to maintain cellular homeostasis as well as to mediate cell communication by spreading protective or injury signals to neighbour or remote cells. In kidney, increasing evidence support that EVs are signalling vesicles for different segments of tubules, intra‐glomerular, glomerular‐tubule and tubule‐interstitial communication. EVs released by kidney resident and infiltrating cells can be isolated from urine and were found to be promising biomarkers for kidney disease, reflecting deterioration of renal function and histological change. We have here summarized the recent progress about the functional role of EVs in kidney disease as well as challenges and future directions involved.     

Polycystic kidney disease: Pathogenesis and potential therapies

Autosomal dominant polycystic kidney disease (ADPKD) is a prevalent, inherited condition for which there is currently no effective specific clinical therapy. The disease is characterized by the progressive development of fluid-filled cysts derived from renal tubular epithelial cells which gradually compress the parenchyma and compromise renal function. Current interests in the field focus on understanding and exploiting signaling mechanisms underlying disease pathogenesis as well as delineating the role of the primary cilium in cystogenesis. This review highlights the pathogenetic pathways underlying renal cyst formation as well as novel therapeutic targets for the treatment of PKD. This article is part of a Special Issue entitled: Polycystic Kidney Disease.     

Renal cystic disease in tuberous sclerosis: role of the polycystic kidney disease 1 gene.

Tuberous sclerosis is an autosomal dominant trait characterized by the development of hamartomatous growths in many organs. Renal cysts are also a frequent manifestation. Major genes for tuberous sclerosis and autosomal dominant polycystic kidney disease, TSC2 and PKD1, respectively, lie adjacent to each other at chromosome 16p13.3, suggesting a role for PKD1 in the etiology of renal cystic disease in tuberous sclerosis. We studied 27 unrelated patients with tuberous sclerosis and renal cystic disease. Clinical histories and radiographic features were reviewed, and renal function was assessed. We sought mutations at the TSC2 and PKD1 loci, using pulsed field- and conventional-gel electrophoresis and FISH. Twenty-two patients had contiguous deletions of TSC2 and PKD1. In 17 patients with constitutional deletions, cystic disease was severe, with early renal insufficiency. One patient with deletion of TSC2 and of only the 3' UTR of PKD1 had few cysts. Four patients were somatic mosaics; the severity of their cystic disease varied considerably. Mosaicism and mild cystic disease also were demonstrated in parents of 3 of the constitutionally deleted patients. Five patients without contiguous deletions had relatively mild cystic disease, 3 of whom had gross rearrangements of TSC2 and 2 in whom no mutation was identified. Significant renal cystic disease in tuberous sclerosis usually reflects mutational involvement of the PKD1 gene, and mosaicism for large deletions of TSC2 and PKD1 is a frequent phenomenon.     

Telocytes: new insight into the pathogenesis of gallstone disease

The major mechanisms of gallstone formation include biliary cholesterol hypersecretion, supersaturation and crystallization, mucus hypersecretion, gel formation and bile stasis. Gallbladder hypomotility seems to be a key event that triggers the precipitation of cholesterol microcrystals from supersaturated lithogenic bile. Telocytes, a new type of interstitial cells, have been recently identified in many organs, including gallbladder. Considering telocyte functions, it is presumed that these cells might be involved in the signalling processes. The purpose of this study was to correlate the quantity of telocytes in the gallbladder with the lithogenicity of bile. Gallbladder specimens were collected from 24 patients who underwent elective laparoscopic cholecystectomy for symptomatic gallstone disease. The control group consisted of 25 consecutive patients who received elective treatment for pancreatic head tumours. Telocytes were visualized in paraffin sections of gallbladders with double immunofluorescence using primary antibodies against c‐Kit (anti‐CD117) and anti‐mast cell tryptase. Cholesterol, phospholipid and bile acid levels were measured in gallbladder bile. The number of telocytes in the gallbladder wall was significantly lower in the study group than that in the control group (3.03 ± 1.43 versus 6.34 ± 1.66 cell/field of view in the muscularis propria, P < 0.001) and correlated with a significant increase in the cholesterol saturation index. The glycocholic and taurocholic acid levels were significantly elevated in the control subjects compared with the study group. The results suggest that bile composition may play an important role in the reduction in telocytes density in the gallbladder.     

Cellular therapies for type 1 diabetes.

Type 1 diabetes mellitus (T1DM) is a disease that results from the selective autoimmune destruction of insulin-producing beta-cells. This disease process lends itself to cellular therapy because of the single cell nature of insulin production. Murine models have provided opportunities for the study of cellular therapies for the treatment of diabetes, including the investigation of islet transplantation, and also the possibility of stem cell therapies and islet regeneration. Studies in islet transplantation have included both allo- and xeno-transplantation and have allowed for the study of new approaches for the reversal of autoimmunity and achieving immune tolerance. Stem cells from hematopoietic sources such as bone marrow and fetal cord blood, as well as from the pancreas, intestine, liver, and spleen promise either new sources of islets or may function as stimulators of islet regeneration. This review will summarize the various cellular interventions investigated as potential treatments of T1DM.     

Structural insight into Parkinson's disease treatment from drug-inhibited DOPA decarboxylase.

DOPA decarboxylase (DDC) is responsible for the synthesis of the key neurotransmitters dopamine and serotonin via decarboxylation of L-3,4-dihydroxyphenylalanine (L-DOPA) and L-5-hydroxytryptophan, respectively. DDC has been implicated in a number of clinic disorders, including Parkinson's disease and hypertension. Peripheral inhibitors of DDC are currently used to treat these diseases. We present the crystal structures of ligand-free DDC and its complex with the anti-Parkinson drug carbiDOPA. The inhibitor is bound to the enzyme by forming a hydrazone linkage with the cofactor, and its catechol ring is deeply buried in the active site cleft. The structures provide the molecular basis for the development of new inhibitors of DDC with better pharmacological characteristics.     

Molecular insight into invasive group A streptococcal disease

Streptococcus pyogenes is also known as group A Streptococcus (GAS) and is an important human pathogen that causes considerable morbidity and mortality worldwide. The GAS serotype M1T1 clone is the most frequently isolated serotype from life-threatening invasive (at a sterile site) infections, such as streptococcal toxic shock-like syndrome and necrotizing fasciitis. Here, we describe the virulence factors and newly discovered molecular events that mediate the in vivo changes from non-invasive GAS serotype M1T1 to the invasive phenotype, and review the invasive-disease trigger for non-M1 GAS. Understanding the molecular basis and mechanism of initiation for streptococcal invasive disease may expedite the discovery of novel therapeutic targets for the treatment and control of severe invasive GAS diseases.     

Cellular oxygen sensing by mitochondria: old questions, new insight.

Hypoxia elicits a variety of adaptive responses at the tissue level, at the cellular level, and at the molecular level. A physiological response to hypoxia requires the existence of an O(2) sensor coupled to a signal transduction system, which in turn activates the functional response. Although much has been learned about the signaling systems activated by hypoxia, no consensus exists regarding the nature of the underlying O(2) sensor or whether multiple sensors exist. Among previously considered mechanisms, heme proteins have been suggested to undergo allosteric modification in response to O(2) binding or release at different PO(2) levels. Other studies suggest that ion channels may change conductance as a function of PO(2), allowing them to signal the onset of hypoxia. Still other studies suggest that NADPH oxidase may decrease its generation of reactive O(2) species (ROS) during hypoxia. Recent data suggest that mitochondria may function as O(2) sensors by increasing their generation of ROS during hypoxia. These oxidant signals appear to act as second messengers in the adaptive responses to hypoxia in a variety of cell types. Such observations contribute to a growing awareness that mitochondria do more than just generate ATP, in that they initiate signaling cascades involved in adaptive responses to hypoxia and that they participate in the control of cell death pathways.     

A new insight into the pathogenesis of filarial disease

Filariasis is a major public health problem throughout many regions of the tropics. The disease is caused by several species of filarial nematode including Wuchereria bancrofti and Brugia malayi, the agents of lymphatic filariasis, and Onchocerca volvulus, the cause of 'riverblindness'. Disease caused by these worms varies depending on the tissue location of the parasite, and is associated with episodes of acute and chronic inflammation. These pathologies, including elephantiasis and blindness, rank among the most disabling in the world. Studies aimed at characterizing the molecular nature of the inflammatory stimuli derived from filarial nematodes uncovered a long forgotten secret, their symbiont Wolbachia. LPS-like molecules from these intracellular bacteria are responsible for potent inflammatory responses from macrophages and in animal models of filarial disease. Wolbachia has also been associated with severe inflammatory reactions to filarial chemotherapy, being released into the blood following the death of the parasite. Recent studies in animal models even implicate Wolbachia in the onset of lymphodema and blindness. Taken together these studies suggest a major role for Wolbachia in the pathogenesis of filarial disease. It may be possible, through the use of antibiotic therapy, to clear worms of their bacteria, in the hope that this will prevent the onset and development of filarial pathology.     

Clinical translation of stem cells: insight for cartilage therapies

Abstract

The limited regenerative capacity of articular cartilage and deficiencies of current treatments have motivated the investigation of new repair technologies. In vitro cartilage generation using primary cell sources is limited by cell availability and expansion potential. Pluripotent stem cells possess the capacity for chondrocytic differentiation and extended expansion, providing a potential future solution to cell-based cartilage regeneration. However, despite successes in producing cartilage using adult and embryonic stem cells, the translation of these technologies to the clinic has been severely limited. This review discusses recent advances in stem cell-based cartilage tissue engineering and the major current limitations to clinical translation of these products. Concerns regarding appropriate animal models and studies, stem cell manufacturing, and relevant regulatory processes and guidelines will be addressed. Understanding the significant hurdles limiting the clinical use of stem cell-based cartilage may guide future developments in the fields of tissue engineering and regenerative medicine.     

Structural insight into insect viruses.

The first structure of an insect picorna-(small RNA-containing) virus is now available. Although there is considerable similarity in the structures of mammalian and insect picornaviruses, there are also remarkable differences, the most noteworthy being associated with the small, internal, functionally essential, VP4 protein.     

Cell-based therapies for experimental chronic kidney disease: a systematic review and meta-analysis

Cell-based therapy is a promising strategy for treating chronic kidney disease (CKD) and is currently the focus of preclinical studies. We performed a systematic review and meta-analysis to evaluate the efficacy of cell-based therapy in preclinical (animal) studies of CKD, and determined factors affecting cell-based therapy efficacy in order to guide future clinical trials. In total, 71 articles met the inclusion criteria. Standardised mean differences (SMD) and 95% confidence intervals (CI) were calculated for outcome parameters including plasma urea, plasma creatinine, urinary protein, blood pressure, glomerular filtration rate, glomerulosclerosis and interstitial fibrosis. Sub-analysis for each outcome measure was performed for model-related factors (species, gender, model and timing of therapy) and cell-related factors (cell type, condition and origin, administration route and regime of therapy). Overall, meta-analysis showed that cell-based therapy reduced the development and progression of CKD. This was most prominent for urinary protein (SMD, 1.34; 95% CI, 1.00–1.68) and urea (1.09; 0.66–1.51), both P<0.001. Changes in plasma urea were associated with changes in both glomerulosclerosis and interstitial fibrosis. Sub-analysis showed that cell type (bone-marrow-derived progenitors and mesenchymal stromal cells being most effective) and administration route (intravenous or renal artery injection) were significant predictors of therapeutic efficacy. The timing of therapy in relation to clinical manifestation of disease, and cell origin and dose, were not associated with efficacy. Our meta-analysis confirms that cell-based therapies improve impaired renal function and morphology in preclinical models of CKD. Our analyses can be used to optimise experimental interventions and thus support both improved preclinical research and development of cell-based therapeutic interventions in a clinical setting.KEY WORDS: Cell-based therapy, Chronic kidney disease, Meta-analysis     

Clinical importance of acquired cystic disease of the kidney in patients undergoing dialysis.

From 1976 to 1982 five patients undergoing haemodialysis at Oxford Renal Unit suffered serious complications from acquired cystic disease of the kidney and two died as a direct result. Clinical features seen were pain, haematuria, palpable renal enlargement, massive haemorrhage, resolution of anaemia, and metastatic malignancy. The clinical histories emphasise the features of a disease that is likely to assume increasing importance in patients undergoing haemodialysis.     

Polycystic kidney disease: novel insights into polycystin function

Autosomal dominant polycystic kidney disease (ADPKD) is a life-threatening monogenic disease caused by mutations in PKD1 and PKD2 that encode polycystin 1 (PC1) and polycystin 2 (PC2). PC1/2 localize to cilia of renal epithelial cells, and their function is believed to embody an inhibitory activity that suppresses the cilia-dependent cyst activation (CDCA) signal. Consequently, PC deficiency results in activation of CDCA and stimulates cyst growth. Recently, re-expression of PCs in established cysts has been shown to reverse PKD. Thus, the mode of action of PCs resembles a ‘counterbalance in cruise control’ to maintain lumen diameter within a designated range. Herein we review recent studies that point to novel arenas for future PC research with therapeutic potential for ADPKD.