Biology subjects

Tan, R. J.

Publications and source records attributed to Tan, R. J..

4 recordsLinked to original sources

bioRxiv2026

An endoplasmic reticulum resident molecular chaperone, GRP170, prevents stress-induced glomerular injury

The glomerulus, a unique capillary network in the nephron, filters an entire blood volume approximately 300 times a day. Specialized epithelial cells known as podocytes form a critical component of the glomerular filtration barrier, and diseases linked to podocyte injury include minimal change disease, focal segmental glomerulosclerosis, and diabetic kidney disease. Because podocytes are terminally differentiated, their ability to respond to external stress is critical. The unfolded protein response (UPR), a cellular stress pathway, is associated with glomerular injury, although the role of the UPR in glomerular injury is undefined. The UPR is initially protective, leading to upregulation of molecular chaperones, a class of proteins that promote protein folding and are required to survive oxidative and ischemic injury. An unresolved UPR, however, leads to apoptosis. We previously found that one molecular chaperone, GRP170, provides protection against acute kidney injury since GRP170 depletion led to UPR induction and widespread kidney injury. Here we generated a new podocyte specific GRP170 knock out mouse (GRP170Pd-/-). Surprisingly, GRP170Pd-/- mice were born healthy, and podocyte development appeared normal. Within a month, however, the knockout mice exhibited profound glomerular injury manifesting as proteinuria, hypoalbuminemia, hyperlipidemia, and kidney injury. Concomitant with glomerular injury, we observed increased expression of the pro-apoptotic UPR target, CHOP, in podocytes. Together, our new model not only defines a protective role for GRP170 against glomerular injury but also provides a new model to test the therapeutic potential of small molecule UPR modulators to treat glomerular injury.

physiology↗

bioRxiv2023

Mineralocorticoid receptor-independent activation of ENaC in bile duct ligated mice

Sodium and fluid retention in liver disease is classically thought to result from reduced effective circulating volume and stimulation of the renin-angiotensin-aldosterone system (RAAS). Aldosterone dives Na+ retention by activating the mineralocorticoid receptor and promoting the maturation and apical surface expression of the epithelial Na+ channel (ENaC), found in the aldosterone-sensitive distal nephron. However, evidence of fluid retention without RAAS activation suggests the involvement of additional mechanisms. Liver disease can greatly increase plasma and urinary bile acid concentrations and have been shown to activate ENaC in vitro. We hypothesize that elevated bile acids in liver disease activate ENaC and drive fluid retention independent of RAAS. We therefore increased circulating bile acids in mice through bile duct ligation (BDL) and measured effects on urine and body composition, while using spironolactone to antagonize the mineralocorticoid receptor. We found BDL lowered blood [K+] and hematocrit, and increased benzamil-sensitive natriuresis compared to sham, consistent with ENaC activation. BDL mice also gained significantly more body water. Blocking ENaC reversed fluid gains in BDL mice but had no effect in shams. In isolated collecting ducts from rabbits, taurocholic acid stimulated net Na+ absorption but had no effect on K+ secretion or flow-dependent ion fluxes. Our results provide experimental evidence for a novel aldosterone-independent mechanism for sodium and fluid retention in liver disease which may provide additional therapeutic options for liver disease patients. SignificanceAdvanced liver disease is often complicated by renal sodium retention, leading to fluid retention, poor outcomes, and increased mortality. This is currently thought to be driven by increased levels of the hormone aldosterone, although numerous published reports demonstrate normal aldosterone levels in many liver patients with volume overload. Management of these patients relies on diuretics and Na+ restriction, or more invasive procedures with increased risks for diuretic-resistant patients. Here, we report a novel mechanism for fluid retention in liver disease, which provides a basis to develop new strategies to treat fluid retention in these patients.

physiology↗

bioRxiv2021

Flexibility of Functional Neuronal Assemblies Supports Human Memory

Summary ParagraphEpisodic memories, or consciously accessible memories of unique events, represent a key aspect of human cognition. Evidence from rodent models suggests that the neural representation of these complex memories requires cooperative firing of groups of neurons on short time scales1, organized by gamma oscillations2, 3. These co-firing groups, termed "neuronal assemblies,"4 represent a fundamental neurophysiological unit supporting memory. Using microelectrode data from neurosurgical patients5, we identify neuronal assemblies in the human MTL and show that they exhibit consistent organization in their firing pattern based on gamma phase information. We connect these properties to memory performance across recording sessions. Finally, we describe how human neuronal assemblies flexibly adjust6-9 over longer time scales. Our findings provide key evidence linking assemblies to human episodic memory for the first time.

neuroscience↗

bioRxiv2020

Direct brain recordings identify hippocampal and cortical networks that distinguish successful versus failed episodic memory retrieval

Human data collected using noninvasive imaging techniques have established the importance of parietal regions towards episodic memory retrieval, including the angular gyrus and posterior cingulate cortex. Such regions comprise part of a putative core episodic retrieval network. In free recall, comparisons between contextually appropriate and inappropriate recall events (i.e. prior list intrusions) provide the opportunity to study memory retrieval networks supporting veridical recall, and existing findings predict that differences in electrical activity in these brain regions should be identified according to the accuracy of recall. However, prior iEEG studies, utilizing principally subdural grid electrodes, have not fully characterized brain activity in parietal regions during memory retrieval and have not examined connectivity between core recollection areas and the hippocampus or prefrontal cortex. Here, we employed a data set obtained from 100 human patients implanted with stereo EEG electrodes for seizure mapping purposes as they performed a free recall task. This data set allowed us to separately analyze activity in midline versus lateral parietal brain regions, and in anterior versus posterior hippocampus, to identify areas in which retrieval-related activity predicted the recollection of a correct versus an incorrect memory. With the wide coverage afforded by the stereo EEG approach, we were also able to examine interregional connectivity. Our key findings were that differences in gamma band activity in the angular gyrus, precuneus, posterior temporal cortex, and posterior (more than anterior) hippocampus discriminated accurate versus inaccurate recall as well as active retrieval versus memory search. The left angular gyrus exhibited a significant power decrease preceding list intrusions as well as unique phase-amplitude coupling properties, whereas the prefrontal cortex was unique in exhibiting a power increase during list intrusions. Analysis of connectivity revealed significant hemispheric asymmetry, with relatively sparse left- sided functional connections compared to the right hemisphere. One exception to this finding was elevated connectivity between the prefrontal cortex and left angular gyrus. This finding is interpreted as evidence for the engagement of prefrontal cortex in memory monitoring and mnemonic decision-making.

neuroscience↗