Journal of Nephrology & Therapeutics

Sec63 is an Hsp40 co-chaperone that is associated with the Sec61 translocon complex in the endoplasmic reticulum. Mutations in SEC63 cause polycystic liver disease in humans. Loss of Sec63 in mice induces cyst formation both in liver and kidney which is mitigated by polycystin-1 (PC1) over expression. We now find that inactivation of Sec63 suppressed G protein–coupled receptor proteolysis site (GPS) cleavage-dependent maturation of PC1, showing an unexpected role of Sec63 in this autoproteolytic process that is critical for cystogenesis. Loss of Sec63 selectively activated the IRE1α-XBP1 branch of the unfolded protein response (UPR), and the inactivation of both Sec63 and XBP1 exacerbated the polycystic kidney phenotype in mice by markedly suppressing GPS cleavage of PC1. Enforced expression of the spliced XBP1s enhanced the GPS cleavage of PC1 in Sec63 deficient cells, suggesting that XBP1 activation normally serves to ameliorate the effects of Sec63 inactivation. XBP1 over expression in vivo ameliorated cystic disease caused by a model of reduced PC1 function unrelated to Sec63, indicating a general protective role of XBP1s activity against cystic diseases resulting from defective PC1 maturation. Selective activation of IRE1α was also achieved by silencing of ERdj4, Sec61α and BiP, but not by depletion of calnexin, calreticulin or Grp94, implicating the dependence of IRE1α activation on select ER chaperones. Collectively, we demonstrated that Sec63 function regulates IRE1α-XBP1 activation that Sec63 and XBP1 control PC1 maturation and that activation of XBP1 can protect against polycystic disease in the setting of impaired maturation of PC1.

Introduction: The cochlea is a metabolically endorgan dependent on nutrient and oxygen supply to maintain its normal physiological function. It is very sensitive to alterations in blood circulation that transient ischemia of the cochlea may result in common otologic disorders. Cochlear ischemia and reperfusion injury has been considered one of the most important causes of human idiopathic sudden sensorineural hearing loss. Ozone is a method in which a gas combination containing ozone and oxygen has been used as a therapeutic agent for the treatment of many diseases. Ozone treatment creates resistance against oxidative stress by inducing antioxidant systems. This research has been conducted to study the efficacy of ozone therapy against cochlear damage because of ischemia and reperfusion, to investigate the potential clinical use of this treatment for sudden deafness. We evaluated cochlear histology and the biochemical parameters characterizing the oxidative stress under ozone treatment. Material and method: 28 Wistar rats were randomized into four groups. Control group (n:7) was administered SF intraperitoneally seven days without creating ischemia reperfusion injury and at eight day the rats were sacrified. Ozone group (n:7) was administered 1 mg/kg ozone intraperitoneally for seven days without creating ischemia reperfusion. 1 mg/kg ozone was administered intraperitoneally for seven days before IR injury in Ischemia Reperfusion (IR)+ Ozone group (I/R+O) (n:7) and at eighth day, these rats were subjected to cochlear ischemia for 15 minutes by occluding left vertebral artery with a nontraumatic clamp and then reperfusion for two hours. Ischemia Reperfusion (IR) group were subjected to cochlear ischemia for 15 minutes by occluding left vertebral artery without ozone therapy. After the ischemia/reperfusion procedure, rats were sacrified at the same day. For general histological evaluation, cochlear and spiral ganglionic tissues were examined with a light microscope and apoptotic cells were counted with TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labeling) staining and apoptotic index (AI) was calculated. Blood samples were sent for superoxide dismutase (SOD), glutation peroxidase (GSH-Px), catalase(CAT), malondyaldehide (MDA), total oxidant score (TOS) and total antioxidant capacity (TAC) analysis. Data were evaluated statistically by Kruskal Wallis test. Results: In ischemia-reperfusion group, the degree of apoptotic index was found highest and statistically significantly compared to the other groups (p<0.05). In the group ischemia reperfusion+ozone (IR+O), apoptotic index was found to be lower in comparison to ischemia reperfusion (IR) group (p<0.05). Antioxidant parameters like SOD, GPX, TAC values were found to be increased in ozone group and lowest in IR group (p<0.05). MDA and TOS oxidant parameters were found to be highest in IR group and decreased in ozone group (p<0.05) . Discussion: Controlled ozone administration was able to stimulate the endogenous antioxidant defense systems and could prepare the host to face ischemia reperfusion injury. Ozone oxidative preconditioning may prevent ischemic tissue reperfusion injury. In the present study, we found a statistically significant decrease in cochlear ischemia reperfusion damage with ozone therapy. Further studies will be necessary to explain the protective mechanisms of ozone therapy on cochlear IR injury.

In 1984 when the National Organ Transplant Act was passed, a more efficient cadaver organ retrieval process might have solved the organ shortage at that time, but the shortage grew faster than the supply. Now we know that organs from the deceased will never meet the current or potential future demand for transplantable organs. The debate over how to increase living organ donation has raged for over 20 years, and become more and more polarized between those who want all donors to be motivated purely by altruism and notions that an incentivized market approach should be implemented. Neither of these approaches is correct. The real answer to how to increase living donation comes from the lessons that can be learned from a most unexpected place Iran the only country in the world without a kidney shortage. Iran has experimented with living organ donation for 30 years. Sigrid Fry-Revere, J.D., PhD traveled to Iran and spent two months interviewing compensated kidney donors. What she learned is that the Iranian system has changed a great deal since its inception, moving ever further away from a market approach. She also learned from her own experience as a potential living donor and recently published studies, that living donors often can’t afford to donate because the incidental nonmedical costs donors and their families face are often prohibitive. The solution, based on lessons from Iran, is to stop thinking of donors as commodities and take their heroism seriously. No payment could ever be enough to compensate someone who gives up part of their body to improve, or even save, the life of another. In the US and in most of the world, we need to start looking at the organ shortage from the donor’s perspective, and find ways to make altruism easier. As in her TEDMED talk in September 2014, Dr. Fry-Revere will describe what Iran has done, particularly how its system has evolved over the past 30 years. And also discuss how the U.S. and other countries can do to greatly increase the number of living donations without creating incentives or a market. By paying more attention to what donors really need not incentives, but a way to donate without their families suffering financially or socially because of the donation.

Estrogen promotes renoprotective effects that are linked to the G-protein-coupled estrogen receptor-1 (GPER-1). Our studies have shown that GPER-1 immunoreactivity is primarily localized in distal convoluted tubules and the Loop of Henle (stained with Tamm-Horsfall Protein-1). Lower GPER-1 expression is observed in proximal convoluted tubules marked with megalin, and GPER-1 is not readily detected in collecting ducts. Plasma membrane fractions prepared from whole kidney tissue or HEK293 cells expressing recombinant human GPER-1 (HEK-GPER-1) display high-affinity, specific [3H]-17β-estradiol ([3H]-E2) binding, but no specific [3H]-aldosterone binding. In contrast, cytosolic preparations exhibit specific binding to [3H]-aldosterone but not to [3H]- E2, consistent with the subcellular distribution of GPER-1 and mineralocorticoid receptor (MR) in these preparations. Aldosterone and MR antagonists, spironolactone and eplerenone, failed to compete for specific [3H]-E2 binding to membranes of HEK-GPER-1 cells. Furthermore, aldosterone did not increase [35S]-GTP-χS binding to membranes of HEK-GPER-1 cells, indicating that it is not involved in G-protein signaling mediated through GPER-1. During the follicular phases of the estrus cycle, GPER-1 is upregulated on renal cortical epithelia and localized to the basolateral surface during proestrus and redistributed intracellularly during estrus. GPER- 1 is down-modulated during the luteal phases of the estrus cycle with significantly less receptor on the surface of renal epithelia, and as measured by gel electrophoretic analysis. Our results demonstrate that GPER-1 is associated with specific estrogen binding and not aldosterone binding and that GPER-1 expression is modulated during the estrus cycle which may suggest a physiological role for GPER-1 in the kidney during reproduction.

Not at all like investigations of resistance following liver transplantation where the paces of operational resilience are fundamentally higher than kidney and the drawn out results of dismissal following immunosuppressive medication decrease or withdrawal restricted with the brief determination and renewed introduction of more escalated immunosuppression, it is commonly believed that unconstrained resistance following kidney transplantation is an uncommon occasion and that scenes of dismissal related with drug withdrawal liable to bargain long haul join capacity and endurance. Along these lines without approved biomarkers of operational resistance most in the field trust it is risky to deliberately pull out immunosuppression except if incited by a clinical sign. Understanding that there were uncommon patients who had stopped all immunosuppression and kept on showing steady, great capacity of the relocated kidney and had subsequently effectively expected the danger independently we picked an examination plan that tried to recognize kidney relocate beneficiaries who had recently halted all immunosuppression. Recognized patients who consented to partake gave segment and clinical information just as natural examples for robotic examines. At the point when possible, only in the setting of living contributor kidney transplantation, endeavors were made to likewise acquire giver cells for extra unthinking tests. Following enlistment subjects went through testing to evaluate renal capacity (serum creatinine and estimation of eGFR), allograft injury (proteinuria and allograft biopsy), alloimmunity (cell measures of insusceptibility and screening for DSA), and more broad investigations to decide the aggregate of fringe platelets by stream cytometry just as quality articulation profiles of fringe platelets (quality cluster and QT-PCR) and shed urinary epithelial cells (QT-PCR). Information and organic examples were acquired from a few extra companions with the end goal of examination.

Acute Kidney Injury (AKI) is defined as a sudden, sustained decline in glomerular filtration rate (GFR), usually associated with uremia and a decline in urine output. The mortality for AKI patients in an ICU setting needing RRT is estimated to be 50% to 70%. Since the introduction of hemodialysis by Kolff in the early 1940s, intermittent renal replacement therapy (IRRT) was offered as a bridge until recovery of kidney function. In the 1980s, Kramer and colleagues introduced continuous renal replacement therapy (CRRT) as an alternative. Since then, few topics in nephrology have been the subject of so many randomized controlled trials (RCTs), meta-analyses and reviews. The theoretical advantages of CRRT mentioned includes, increased time-averaged dialysis dose, less hemodynamic instability and removal of high molecular weight solutes such as inflammatory cytokines. From its early days, questions were raised as to which of CRRT or IRRT was related to better outcomes. The general perception was that the continuous approach, due to its slow protracted nature, would result in better outcomes. At least seven published RCTs and three meta-analyses were unable to demonstrate a difference in outcome between both approaches, with a reported relative risk of 0.99. The Cochrane Meta analysis of 15 studies (1550 patients) showed that CRRT did not differ from IRRT with respect to in-hospital mortality, ICU mortality, and number of surviving patients not requiring RRT, hemodynamic instability or hypotension needing escalation of Pressor therapy. Patients on CRRT were likely to have significantly higher mean arterial pressure (MAP) and higher risk of clotting dialysis filters. The application of CRRT in combating severe fluid overload is widely popular despite the evidence. CRRT has also been proposed as the preferred option for combined acute renal and hepatic failure and acute brain injury because of prevention of cerebral edema. Arguments in favour of IRRT are practical considerations like user-friendliness, limitation of expenses, restriction of bleeding complications; and small solute removal in acute life threatening conditions. In summary, CRRT and IRRT are equivalent dialysis strategies. Both therapeutic strategies should not be considered as competitors, but rather as alternatives, usage depending on the unit expertise and the metabolic or the fluid balance needs of the patient.