The impact of bladder filling rate on cystometric outcomes remains unclear. Clinically, faster bladder filling is believed to increase the likelihood of observing detrusor overactivity (DO) in those with bladder dysfunction, although evidence of this is lacking. We executed this study to clarify how changes in bladder filling rate impact cystometric parameters. Urethane-anesthetized female CD rats ( = 19) underwent bladder filling at five different fill rates, a baseline rate scaled to have a filling phase of ∼7 min (in line with our previous work) and scaled rates of 1/3×, 2×, 4×, and 8× that speed. Contrary to expectations, filling at faster rates decreased the likelihood of observing detrusor overactivity, with 4× and 8× filling rates demonstrating less detrusor overactivity than the baseline (1×) rate ( = 0.0091 for 4× and = 0.019 for 8×). However, faster filling rates did decrease bladder compliance. Filling at 4× and 8× demonstrated decreased bladder compliance compared to 1× ( = 0.032 for 4× and < 0.0001 for 8×). Finally, increasing the filling rate led to increases in bladder capacity at 4× ( = 0.034) and 8× ( = 0.0066) relative to 1×. These results suggest that, contrary to expectations, faster filling may not be more effective at eliciting detrusor overactivity (i.e., not a better diagnostic approach). As reductions in detrusor overactivity and increases in bladder capacity are critical parameters for evaluating preclinical therapeutics, faster filling may impair the ability to demonstrate further improvements. Little is known about the effects of different bladder filling rates on cystometric results. Various sources have suggested that faster filling is "provocative" to the bladder. However, in this study we varied bladder filling rates in anesthetized rats and observed less detrusor overactivity with faster filling, not more. We explain this discrepancy as a miscommunication about what being provocative means, where faster filling leads to worse bladder compliance (as we observed), not more detrusor overactivity.

In the present study, we examined whether chronic intracerebroventricular (ICV) leptin administration protects against ischemia/reperfusion (I/R)-induced acute kidney injury (AKI). Twelve-week-old male rats were implanted with an ICV cannula into the right lateral ventricle, and 8-10 days after surgery, leptin (0.021 µg/h, = 8) or saline vehicle (0.5 µL/h, = 8) was infused via osmotic minipump connected to the ICV cannula for 12 days. On of leptin or vehicle infusion, rats were submitted to unilateral ischemia/reperfusion (UIR) by clamping the left pedicle for 30 min. To control for leptin-induced reductions in food intake, the vehicle-treated group was pair-fed (UIR-PF) to match the same amount of food consumed by leptin-treated (UIR-Leptin) rats. On the 12th day of leptin or vehicle infusion (fourth day after AKI), single-left kidney glomerular filtration rate (GFR) was measured, blood samples were collected to quantify white blood cells, and kidneys were collected for histological assessment of injury. UIR-Leptin-treated rats showed reduced right and left kidney weights (right: 1,040 ± 24 vs. 1,281 ± 36 mg; left: 1,127 ± 71 vs. 1,707 ± 45 mg, for UIR-Leptin and UIR-PF, respectively). ICV leptin infusion improved GFR (0.50 ± 0.06 vs. 0.13 ± 0.03 mL/min/g kidney wt) and reduced kidney injury scores. ICV leptin treatment also attenuated the reduction in circulating adiponectin levels that was observed in UIR-PF rats and increased the circulating white blood cells count compared with UIR-PF rats (16.3 ± 1.3 vs. 9.8 ± 0.6 k/µL). Therefore, we show that leptin, via its actions on the central nervous system, confers significant protection against major kidney dysfunction and injury in a model of ischemia/reperfusion-induced AKI. A major new finding of this study is that chronic activation of leptin receptors in the CNS markedly attenuates acute kidney injury and protects against severe renal dysfunction after ischemia/reperfusion, independently of leptin's anorexic effects.

Cardiac surgery-associated acute kidney injury (CSA-AKI) is a high-risk complication with well-recognized increased morbidity and mortality after cardiac surgery attributable in large part to cardiopulmonary bypass (CPB)-associated factors contributing to AKI including hemodilution, hypothermia, hypotension, and exposure to artificial surfaces. These conditions disrupt the renal microcirculation and activate local and systemic inflammatory responses to nonpulsatile flow and low perfusion pressure. The underlying mechanisms of CSA-AKI in CPB are not fully understood, and the incidence of CSA-AKI remains high at around 30%. Furthermore, women appear to be more vulnerable than men to the renal injury associated with CPB even though the overall incidence of cardiovascular and kidney diseases is lower in premenopausal women. Nevertheless, estrogen elicits renoprotective effects in several ways including mitigating inflammation, promoting natriuresis, and endothelial protection as shown in preclinical studies. However, women have higher rates of CSA-AKI and these are exacerbated in postmenopausal women. This leads to the conundrum of whether sex, age, and hormonal status differences influence CSA-AKI. In this review, we briefly discuss the pathophysiology of CSA-AKI in CPB and sex differences in kidney functions with a focus on the possible role of estrogen-specific effects in CPB and also possible differences in CPB in women including greater hemodilution. Furthermore, we review strategies to prevent CSA-AKI in CPB with a highlight for potential sex-specific strategies. Improving our understanding of the impact of sex and sex hormones on CSA-AKI initiation and development will allow us to better manage the CPB strategies delivered to all patients.

In the proximal tubules of the kidney, angiotensin II (ANG II) binds and activates ANG II type 1 (AT) receptors to stimulate proximal tubule Na reabsorption, whereas atrial natriuretic peptide (ANP) binds and activates natriuretic peptide receptors (NPR) to inhibit ANG II-induced proximal tubule Na reabsorption. These two vasoactive systems play important counteracting roles to control Na reabsorption in the proximal tubules and help maintain blood pressure homeostasis. However, how AT and NPR receptors interact in the proximal tubules and whether natriuretic effects of NPR receptor activation by ANP may be potentiated by deletion of AT (AT) receptors selectively in the proximal tubules have not been studied previously. The present study used a novel mouse model with proximal tubule-specific knockout of AT receptors, PT-, to test the hypothesis that deletion of AT receptors selectively in the proximal tubules augments the hypotensive and natriuretic responses to ANP. Basal blood pressure was about 16 ± 3 mmHg lower ( < 0.01), fractional proximal tubule Na reabsorption was significantly lower ( < 0.05), whereas 24-h urinary Na excretion was significantly higher, in PT- mice than in wild-type mice ( < 0.01). Infusion of ANP via osmotic minipump for 2 wk (0.5 mg/kg/day ip) further significantly decreased blood pressure and increased the natriuretic response in PT- mice by inhibiting proximal tubule Na reabsorption compared with wild-type mice ( < 0.01). These augmented hypotensive and natriuretic responses to ANP in PT- mice were associated with increased plasma and kidney cGMP levels ( < 0.01), kidney cortical NPR and NPR mRNA expression ( < 0.05), endothelial nitric oxide (NO) synthase (eNOS) and phosphorylated eNOS proteins ( < 0.01), and urinary NO excretion ( < 0.01). Taken together, the results of the present study provide further evidence for important physiological roles of intratubular ANG II/AT and ANP/NPR signaling pathways in the proximal tubules to regulate proximal tubule Na reabsorption and maintain blood pressure homeostasis. This study used a mutant mouse model with proximal tubule-selective deletion of angiotensin II (ANG II) type 1 (AT) receptors to study, for the first time, important interactions between ANG II/AT (AT) receptor/Na/H exchanger 3 and atrial natriuretic peptide (ANP)/natriuretic peptide receptor (NPR)/cGMP/nitric oxide signaling pathways in the proximal tubules. The results of the present study provide further evidence for important physiological roles of proximal tubule ANG II/AT and ANP/NPR signaling pathways in the regulation of proximal tubule Na reabsorption and blood pressure homeostasis.

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases with important roles in kidney homeostasis and pathology. While capable of collectively degrading each component of the extracellular matrix, MMPs also degrade nonmatrix substrates to regulate inflammation, epithelial plasticity, proliferation, apoptosis, and angiogenesis. More recently, intriguing mechanisms that directly alter podocyte biology have been described. There is now irrefutable evidence for MMP dysregulation in many types of kidney disease including acute kidney injury, diabetic and hypertensive nephropathy, polycystic kidney disease, and Alport syndrome. This updated review will detail the complex biology of MMPs in kidney disease.

Aristolochic acid (AA) ingestion causes Balkan nephropathy, characterized by tubular injury and progression to chronic kidney disease (CKD). AA is taken up by proximal tubule cells via organic anion transport and induces p21-mediated DNA damage response, but little is known about dietary modulating factors. Western diet (WD) is rich in saturated fats and sugars and can promote metabolic disorders and CKD progression. Here we determined the impact of WD on AA-induced kidney injury. 5-week-old male C57BL/6J mice were fed WD or normal chow (NC) for 8 weeks, followed by administration of AA every 3 days for 3 weeks. Measurements were performed after the last injection and following a 3-week recovery. Independent of dosing AA by body weight (3 mg/kg/day) or same dose/mouse (0.1125 mg/day), the AA-induced increase in plasma creatinine and reduction of hematocrit were greater in WD vs NC. This was associated with increased kidney gene expression in WD vs NC of markers of DNA damage (p21), injury (Kim1 and Ngal), and inflammation (Tnfa) as well as kidney fibrosis staining. WD alone increased fractional excretion of indoxyl sulfate by 7.5 fold, indicating enhanced kidney organic anion transport. Kidney proteomics identified further WD-induced changes that could increase kidney sensitivity to AA and contribute to the altered response to AA including weakening of energy metabolism, potentiation of immune and infection pathways, and disruption in RNA regulation. In conclusion, WD can increase the susceptibility of mice to Balkan nephropathy, possibly in part through facilitating kidney uptake of the organic anion AA.

Epidermal growth factor (EGF) has important effects in the renal collecting duct to regulate salt and water transport. To identify elements of EGF-mediated signaling in the rat renal inner medullary collecting duct (IMCD), we carried out phosphoproteomics analysis. Biochemically isolated rat IMCD suspensions were treated with 1 μM of EGF or vehicle for 30 min. We performed comprehensive quantitative phosphoproteomics using TMT-labeling of tryptic peptides followed by protein mass spectrometry. We present a data resource reporting all detected phosphorylation sites and their changes in response to EGF. For a total of 29,881 unique phosphorylation sites, 135 sites were increased and 119 sites were decreased based on stringent statistical analysis. The data are provided to users at https://esbl.nhlbi.nih.gov/Databases/EGF-phospho/. Analysis demonstrated that EGF signals through canonical EGF pathways in the renal IMCD. Analysis of KEGG pathways in which EGF-regulated phosphoproteins are over-represented in native rat IMCD cells confirmed mapping to RAF-MEK-ERK signaling, but also pointed to a role for EGF in the regulation of protein translation. A large number of phosphoproteins regulated by EGF contained PDZ domains that are key elements of epithelial polarity determination. We also provide a collecting duct EGF-network map as a user accessible web resource at https://esbl.nhlbi.nih.gov/Databases/EGF-network/. Overall, the phosphoproteomic data presented provide a useful resource for experimental design and modeling of signaling in the renal collecting duct.

Epithelial sodium channel (ENaC) represents a major route of Na reabsorption in the aldosterone-sensitive distal nephron where the bulk of ENaC activity is considered to occur in the cortical collecting duct (CCD). Relatively, ENaC activity in the medulla, especially the inner medulla, is often neglected. (Pro)renin receptor (PRR), also termed as ATP6AP2, a newly characterized member of the renin-angiotensin system (RAS), has emerged as an important regulator of ENaC in the distal nephron. The ENaC regulatory action of PRR is largely mediated by the 28 kDa soluble PRR (sPRR). Although all three subunits of ENaC are under the control of aldosterone, sPRR only mediates the upregulation of α-ENaC but not the other two subunits. Furthermore, sPRR-dependent regulation of α-ENaC only occur in the renal inner medulla but not the cortex. sPRR also rapidly upregulates ENaC activity via Nox4-derived HO. Overall, sPRR has emerged as an important regulator of renal medullary Na reabsorption in the context of overactivation of the renin-angiotensin-aldosterone system (RAAS).

Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular disease (CVD). Despite the entry of sodium glucose cotransporter 2 (SGLT2) inhibitors, CKD persists as a medical challenge. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition reduces low-density lipoprotein (LDL)-cholesterol, a major risk factor of CVD. Interestingly, studies indicate that PCSK9 inhibition decreases proteinuria in kidney disease, complementing the reduced CVD risk. This study aimed to validate obese ZSF1 rats as a model for the renoprotective effects of PCSK9 and SGLT2 inhibition using alirocumab and empagliflozin for 15 weeks. Obese rats revealed a significant reduction in measured glomerular filtration rate (mGFR) and increased urine albumin/creatinine ratio (UACR) during follow-up compared to lean controls. Alirocumab treatment resulted in a decline in mGFR and increased UACR compared to vehicle-treated obese rats. Immunohistochemistry showed increased fibrosis and inflammation in kidney tissue from obese rats treated with empagliflozin or alirocumab, whereas hepatic cholesterol and triglyceride levels were lowered compared to vehicle-treated obese rats. While alirocumab lowered circulating free cholesterol levels throughout the treatment period, certain cholesteryl esters were increased at the end of the study, resulting in no overall difference in total cholesterol levels in the alirocumab group. Correspondingly, only a trend toward increased hepatic LDL-receptor levels was observed. In conclusion, these findings suggest that alirocumab treatment aggravates kidney dysfunction in obese ZSF1 rats. Moreover, in contrast to the renoprotective properties of empagliflozin observed in CKD patients, empagliflozin did not ameliorate kidney disease progression in the obese ZSF1 rat.

The maintenance of fluid and electrolyte homeostasis by the kidney requires proper folding and trafficking of ion channels and transporters in kidney epithelia. Each of these processes requires a specific subset of a diverse class of proteins termed molecular chaperones. One such chaperone is GRP170, which is an Hsp70-like, endoplasmic reticulum (ER)-localized chaperone that plays roles in protein quality control and protein folding in the ER. We previously determined that loss of GRP170 in the mouse nephron leads to hypovolemia, electrolyte imbalance, and rapid weight loss. In addition, GRP170-deficient mice develop an AKI-like phenotype, typified by tubular injury, elevation of kidney injury markers, and induction of the unfolded protein response (UPR). By using an inducible GRP170 knockout cellular model, we confirmed that GRP170 depletion induces the UPR, triggers apoptosis, and disrupts protein homeostasis. Based on these data, we hypothesized that UPR induction underlies hyponatremia and volume depletion in these rodents, and that these and other phenotypes might be rectified by sodium supplementation. To test this hypothesis, control and GRP170 tubule-specific knockout mice were provided a diet containing 8% sodium chloride. We discovered that sodium supplementation improved electrolyte imbalance and kidney injury markers in a sex-specific manner but was unable to restore weight or tubule integrity. These results are consistent with UPR induction contributing to the kidney injury phenotype in the nephron-specific GR170 knockout model and indicate that GRP170 function in kidney epithelia is essential to both maintain electrolyte balance and ER homeostasis.

Here, we review key events in the accrual of knowledge about the cortical thick ascending limb (CTAL) of the kidney, starting with its initial characterization by Maurice Burg in 1973. Burg's work showed that the CTAL actively reabsorbs NaCl and that, because its water permeability is virtually zero, it can lower the luminal NaCl concentration to a 'static head' level well below blood levels. This process is central to the kidney's ability to excrete a dilute urine in states of high water intake. Following Burg's original observations, Greger and Schlatter, working in the 1980's, identified the membrane transport processes responsible for transepithelial NaCl transport in the CTAL. In the 1990's, several investigators identified the key transporter genes and proteins at a molecular level by cDNA cloning. The successful completion of human and mouse genome sequencing projects at the turn of the century, led to development of transcriptomic and proteomic methodologies that allowed identification of complete transcriptomes and proteomes of CTAL cells. Knowledge accrual was enhanced by the development of differential equation-based models of transport in the CTAL in the 2010's. Here we used a simplified mathematical model of NaCl ('salt'), urea and water transport in the CTAL to address three key questions about CTAL function: 1) What is the mechanism of Burg's 'static head' phenomenon? 2) How does the kidney compensate for the very short length of the CTALs of juxtamedullary nephrons? 3) Which of the three isoforms of the apical Na-K-2Cl cotransporter (NKCC2) dominates functionally in the CTAL?

Biobanking of tissue from clinically obtained kidney biopsies for later analysis with multiomic approaches, such as single-cell technologies, proteomics, metabolomics, and the different types of imaging, is an inevitable step to overcome the need of disease model systems and toward translational medicine. Hence, collection protocols that ensure integration into daily clinical routines by the usage of preservation media that do not require liquid nitrogen but instantly preserve kidney tissue for both clinical and scientific analyses are necessary. Thus, we modified a robust single-nucleus dissociation protocol for kidney tissue stored snap-frozen or in the preservation media RNAlater and CellCover. Using at first porcine kidney tissue as a surrogate for human kidney tissue, we conducted single-nucleus RNA sequencing with the widely recognized Chromium 10X Genomics platform. The resulting datasets from each storage condition were analyzed to identify any potential variations in transcriptomic profiles. Furthermore, we assessed the suitability of the preservation media for additional analysis techniques such as proteomics, metabolomics, and the preservation of tissue architecture for histopathological examination including immunofluorescence staining. In this study, we show that in daily clinical routines, the preservation medium RNAlater facilitates the collection of highly preserved human kidney biopsies and enables further analysis with cutting-edge techniques like single-nucleus RNA sequencing, proteomics, and histopathological evaluation. Only metabolome analysis is currently restricted to snap-frozen tissue. This work will contribute to build tissue biobanks with well-defined cohorts of the respective kidney disease that can be deeply molecularly characterized, opening up new horizons for the identification of unique cells, pathways and biomarkers for the prevention, early identification, and targeted therapy of kidney diseases. In this study, we addressed challenges in integrating clinically obtained kidney biopsies into everyday clinical routines. Using porcine kidneys, we evaluated preservation media (RNAlater and CellCover) versus snap freezing for multi-omics processing. Our analyses highlighted RNAlater's suitability for single-nucleus RNA sequencing, proteome analysis and histopathological evaluation. Only metabolomics are currently restricted to snap-frozen biopsies. Our research established a cryopreservation protocol that facilitates tissue biobanking for advancing precision medicine in nephrology.

In the kidney, the thick Ascending Limb (TAL) of the loop of Henle is crucial for NaCl homeostasis and blood pressure regulation. In animal models of salt-sensitive hypertension, NaCl reabsorption the apical Na+/K+/2Cl cotransporter (NKCC2) is abnormally increased in the TAL. We showed that NaCl reabsorption is controlled by the presence of NKCC2 at the apical surface of TALs. However, the molecular mechanisms that maintain the steady-state levels of NKCC2 at the apical surface are not clearly understood. Here, we report that NKCC2 interacts with the F-actin cross-linking protein actinin-4 (ACTN4). We find that ACTN4 is expressed in TALs by Western blot and immunofluorescence microscopy. ACTN4 immunoprecipitated with NKCC2 and recombinant GST-ACTN4 pulled down NKCC2 from TAL lysates. ACTN4 is involved in endocytosis in other cells. Therefore, we hypothesized that ACTN4 binds apical NKCC2 and regulates its trafficking. To study this, we silenced ACTN4 via shRNA or CRISPR/Cas9 system to decrease ACTN4 expression in TALs. We observed that silencing ACTN4 via shRNA or CRISPR/Cas9 system increased the amount NKCC2 at the apical surface of TALs. Bumetanide-induced diuresis and natriuresis were enhanced by 35% after silencing of ACTN4 in vivo (AV-NKCC2-Cas9: 3841±709 vs AAV-gRNA-ACTN4: 5546±622 µmols Na/8h, n=5, p<0.05). We conclude that ACTN4, binds NKCC2 to regulate its surface expression. Selective depletion of ACTN4 in TALs using shRNA or CRISPR/Cas9 enhances surface NKCC2 and TAL NaCl reabsorption, indicating that regulation of the ACTN4-NKCC2 interaction is important for renal NaCl reabsorption and could be related to hypertension.

A considerable amount of NaCl reabsorption in proximal tubules (PTs) occurs the paracellular transport regulated by the tight junction proteins claudins (Cldns). However, the paracellular transport properties in mouse superficial PTs remain unclear. We characterized these properties in superficial PT S1-S3 segments from mice expressing [wild-type (WT, WTS1-WTS3)] or lacking claudin-2 [knockout (KO, KOS1-KOS3)]. We isolated and perfused segments with symmetrical solutions in the presence of bath ouabain and measured the diffusion potential upon changing the salt composition of the lumen or bath. Based on the diffusion potential corrected for the liquid junction potential (dV), we calculated the paracellular Na over Cl permeability (P/P) ratio. The P/P values upon reducing luminal NaCl averaged 1.27, 1.04, and 0.85 in WTS1, WTS2, and WTS3 and 0.34, 0.55, and 0.80 in KOS1, KOS2, and KOS3, respectively. The dV values exhibited a symmetrical response to bidirectional NaCl concentration gradients in WTS1-WTS3 and KOS1-KOS3. WTS1 and WTS3 were monovalent cation-selective, with WTS1 demonstrating stronger cation selectivity. The order of permeabilities relative to Cl was K > Rb > Na > Li, whereas both KOS1 and KOS3 exhibited monovalent cation selectivity loss and consequently enhanced anion selectivity, especially in KOS1. Protamine addition to the lumen and bath similarly decreased P/P values upon reduced luminal NaCl in the order of WTS1 > WTS3 > KOS3 > KOS1. Therefore, this study presents evidence of axial heterogeneity in paracellular transport across superficial PTs in mice.

Brain and muscle ARNT-Like 1 (BMAL1) is a circadian clock transcription factor that regulates physiological functions. Male adrenal-specific () KO mice displayed blunted serum corticosterone rhythms, altered blood pressure rhythm, and altered timing of eating, but there is a lack of knowledge in females. This study investigates the role of adrenal BMAL1 in renal electrolyte handling and urinary aldosterone levels in response to low salt in male and female mice. Mice were placed in metabolic cages to measure 12-hour urinary aldosterone after a standard diet and 7 days low salt diet, as well as daily body weight, 12-hour food and water intake, and renal sodium and potassium balance. Adrenal glands and kidneys were collected at ZT0 or ZT12 to measure expression of aldosterone synthesis genes and clock genes. Compared to littermate controls, KO male and female mice displayed increased urinary aldosterone in response to a low salt diet, although mRNA expression of aldosterone synthesis genes was decreased. Timing of food intake was altered in KO male and female mice, with a blunted night/day ratio. KO female mice displayed decreases in renal sodium excretion in response to low salt, but both male and female KO mice had changes in sodium balance that were time-of-day-dependent. In addition, sex differences were found in adrenal and kidney clock gene expression. Notably, this study highlights sex differences in clock gene expression that could contribute to sex differences in physiological functions.

Blood glucose homeostasis is critical to ensure the proper functioning of the human body. Through the processes of filtration, reabsorption, secretion, and metabolism, much of this task falls to the kidneys. With a rise in glucose and other added sugars, there is an increased burden on this organ, mainly the proximal tubule which is responsible for all glucose reabsorption. In this review, we focus on the current physiological and cell biological functions of the renal proximal tubule as it works to reabsorb and metabolize glucose and fructose. We also highlight the physiological adaptations that occur within the proximal tubule as sugar levels rise under pathophysiological conditions including diabetes. This includes the detrimental impacts of an excess glucose load that leads to glucotoxicity. Finally, we explore some of the emerging therapeutics that modulate renal glucose handling and the systemic protection that can be realized by targeting the reabsorptive properties of the kidney.

In previously published work, we elucidated the role of cutaneous arsenical exposure in promoting acute kidney injury (AKI) in adult healthy mice. Here, we determine whether pre-existing chronic kidney disease (CKD) increases the severity of AKI. Following exposure to aristolochic acid (AA) (a nephrotoxic phytochemical in humans), mice manifested classical markers of CKD, including robust interstitial fibrosis and loss in kidney function. Skin challenge with phenylarsine oxide (PAO), a surrogate for warfare arsenicals, led to significantly worse kidney injury, as evidenced by tubulointerstitial fibrosis, glomerulosclerosis, a persistent loss of estimated glomerular filtration rate and mortality in AA-induced CKD mice compared to mice without CKD. These PAO-challenged CKD mice exhibited enhanced production of serum/urine NGAL, and a significant rise in serum creatinine along with histological markers of kidney injury, including brush border loss, tubular atrophy, cast formation, glomerular injury, and interstitial inflammatory cell infiltration Serum cytokines IL-4, IL-6, IFN-γ, IL-12p70, TNF-α, and IL-18 significantly elevated in CKD mice following PAO exposure when compared to animals exposed to PAO alone. Furthermore, we found increased TUNEL-positive tubular cells in the kidneys of CKD mice following PAO exposure, suggesting enhanced PAO-mediated cell death in CKD mice. Mechanistically, we determined that DNA damage-regulated p53 signaling was a major mediator of cellular responses to PAO in CKD mice. In summary, our data demonstrate that CKD significantly increased severity of AKI following exposure to arsenicals and suggest that human populations with preexisting CKD could be highly susceptible to arsenical-mediated kidney injury and associated morbidity and mortality.

High Na intake has been linked to elevations in blood pressure, whereas K has the opposite effect. The underlying mechanisms involve complex interactions among renal function, fluid volume, fluid-regulatory hormones, the vasculature, cardiac function, and the autonomic nervous system. These mechanisms are likely moderated by sex, given the known sex differences in blood pressure regulation and the higher prevalence of hypertension in men. The source of these observed sex differences may be traced to organ and tissue levels, given that kidney function, intrarenal renin-angiotensin system components, renal sympathetic nervous activity, and nitric oxide bioavailability all exhibit sex differences. To assess the functional impact of each of these sex differences, we developed sex-specific computational models to simulate whole-body Na, K, and fluid homeostasis, and the effects on blood pressure. The models describe the interactions among the renal system, cardiovascular system, gastrointestinal system, renal sympathetic nervous system, and renin-angiotensin-aldosterone system. Model simulations suggest that women's attenuated blood pressure response to hypertensive stimuli, including high Na intake, may be largely attributable to the female renal transporter abundance pattern. Additionally, we investigated the causal link between high K intake and blood pressure reduction. The models simulate renal response to high K intake, including the immediate gastrointestinal feedforward signals to the kidneys to increase K excretion, and the longer-term response to decrease proximal fractional Na reabsorption and distal K reabsorption. With these assumptions, simulations of high K intake yielded kaliuresis, natriuresis, and a substantial reduction in blood pressure, even when combined with high Na intake.

Maternal caloric restriction during pregnancy significantly impacts kidney development, influencing susceptibility to chronic kidney disease in adulthood. This study explores DNA methylation changes in nephron progenitor cells resulting from caloric restriction and their implications for kidney health. Global DNA hypomethylation is observed in nephron progenitors from caloric-restricted embryos, with specific genomic regions displaying distinct methylation patterns, including hypomethylation and hypermethylation. Differentially methylated regions exhibit enhanced chromatin accessibility, indicating biological relevance. Hypomethylated regions are enriched for genes associated with developmental processes, reflecting changes in gene expression and highlighting their functional relevance in kidney development. The study also reveals that supplementing methionine, an essential amino acid, restores disrupted DNA methylation patterns, particularly in enhancer regions, emphasizing methionine's critical role in regulating nephron progenitor cell epigenetics and ensuring proper kidney development. The intricate relationship between maternal nutrition, dynamic DNA methylation, and kidney development is highlighted, emphasizing the enduring impact of early-life nutritional challenges on kidney function. This research elucidates epigenetic mechanisms as mediators for the lasting effects of maternal caloric restriction on kidney health. The study contributes valuable insights into the origins of chronic kidney diseases during early developmental stages, offering potential interventions to mitigate adverse outcomes.

The susceptibility of patients with chronic kidney disease (CKD) to develop postprandial hyperkalemia suggests alterations in normal kidney sodium (Na) and potassium (K) handling, but the exact nature of these changes is largely unknown. To address this, we analyzed the natriuretic and kaliuretic responses to diuretics and acute K loading in rats who underwent 5/6 nephrectomy (5/6Nx) and compared this to the response in sham-operated rats. The natriuretic and kaliuretic responses to furosemide, hydrochlorothiazide, and amiloride were largely similar between 5/6Nx and sham rats except for a significantly reduced kaliuretic response to hydrochlorothiazide in 5/6Nx rats. Acute dietary K loading with either 2.5% potassium chloride or 2.5% potassium citrate caused lower natriuretic and kaliuretic responses in 5/6Nx rats compared with sham rats. This resulted in significantly higher plasma K concentrations in 5/6Nx rats which were accompanied by corresponding increases in plasma aldosterone. Acute K loading caused dephosphorylation of Ste20-related proline/alanine-rich kinase (SPAK) and the sodium-chloride cotransporter (NCC) both in sham and 5/6Nx rats. In contrast, the acute K load decreased the Na/hydrogen exchanger 3 (NHE3) and increased serum- and glucocorticoid-regulated kinase 1 (SGK1) and the α-subunit of the epithelial sodium channel (ENaC) only in sham rats. Together, our data show that 5/6Nx impairs the natriuretic and kaliuretic response to an acute dietary K load which is further characterized by a loss of ENaC adaptation and the development of postprandial hyperkalemia.