Renal Handling Research Articles

A mathematical model of potassium homeostasis: Effect of feedforward and feedback controls.

Maintaining normal potassium (K+) concentrations in the extra- and intracellular fluid is critical for cell function. K+ homeostasis is achieved by ensuring proper distribution between extra- and intracellular fluid compartments and by matching K+ excretion with intake. The Na+-K+-ATPase pump facilitates K+ uptake into the skeletal muscle, where most K+ is stored. Na+-K+-ATPase activity is stimulated by insulin and aldosterone. The kidneys regulate long term K+ homeostasis by controlling the amount of K+ excreted through urine. Renal handling of K+ is mediated by a number of regulatory mechanisms, including an aldosterone-mediated feedback control, in which high extracellular K+ concentration stimulates aldosterone secretion, which enhances urine K+ excretion, and a gastrointestinal feedforward control mechanism, in which dietary K+ intake increases K+ excretion. Recently, a muscle-kidney cross talk signal has been hypothesized, where the K+ concentration in skeletal muscle cells directly affects urine K+ excretion without changes in extracellular K+ concentration. To understand how these mechanisms coordinate under different K+ challenges, we have developed a compartmental model of whole-body K+ regulation. The model represents the intra- and extracellular fluid compartments in a human (male) as well as a detailed kidney compartment. We included (i) the gastrointestinal feedforward control mechanism, (ii) the effect of insulin and (iii) aldosterone on Na+-K+-ATPase K+ uptake, and (iv) aldosterone stimulation of renal K+ secretion. We used this model to investigate the impact of regulatory mechanisms on K+ homeostasis. Model predictions showed how the regulatory mechanisms synthesize to ensure that the extra- and intracelluller fluid K+ concentrations remain in normal range in times of K+ loading and fasting. Additionally, we predict that without the hypothesized muscle-kidney cross talk signal, the model was unable to predict a return to normal extracellular K+ concentration after a period of high K+ loading or depletion.

Genetically inducing renal lymphangiogenesis attenuates hypertension in mice.

Hypertension (HTN) is associated with renal proinflammatory immune cell infiltration and increased sodium retention. We reported previously that renal lymphatic vessels, which are responsible for trafficking immune cells from the interstitial space to draining lymph nodes, increase in density under hypertensive conditions. We also demonstrated that augmenting renal lymphatic density can prevent HTN in mice. Whether renal lymphangiogenesis can treat HTN in mice is unknown. We hypothesized that genetically inducing renal lymphangiogenesis after the establishment of HTN would attenuate HTN in male and female mice from three different HTN models. Mice with inducible kidney-specific overexpression of VEGF-D (KidVD) experience renal lymphangiogenesis upon doxycycline administration. HTN was induced in KidVD+ and KidVD- mice by subcutaneous release of angiotensin II, administration of the nitric oxide synthase inhibitor L-NAME, or consumption of a 4% salt diet following a L-NAME priming and washout period. After a week of HTN stimuli treatment, doxycycline was introduced. Systolic blood pressure (SBP) readings were taken weekly. Kidney function was determined from urine and serum measures. Kidneys were processed for RT-qPCR, flow cytometry, and imaging. Mice that underwent renal-specific lymphangiogenesis had significantly decreased SBP and renal proinflammatory immune cells. Additionally, renal lymphangiogenesis was associated with a decrease in sodium transporter expression and increased fractional excretion of sodium, indicating improved sodium handling efficiency. These findings demonstrate that augmenting renal lymphangiogenesis can treat HTN in male and female mice by improving renal immune cell trafficking and sodium handling.

Dicarbonyl-modified lipoproteins contribute to proteinuric kidney injury.

Lipoprotein modification by reactive dicarbonyls, including isolevuglandin (IsoLG), produces dysfunctional particles. Kidneys participate in lipoprotein metabolism, including tubular uptake. However, the process beyond the proximal tubule is unclear, as is the effect of kidney injury on this pathway. We found that patients and animals with proteinuric injury have increased urinary apolipoprotein AI (apoAI), IsoLG, and IsoLG adduct enrichment of the urinary apoAI fraction compared with other proteins. Proteinuric mice, induced by podocyte-specific injury, showed more tubular absorption of IsoLG-apoAI and increased expression of lipoprotein transporters in proximal tubular cells compared with uninjured animals. Renal lymph reflects composition of the interstitial compartment and showed increased apoAI and IsoLG in proteinuric animals, supporting a tubular cell-interstitium-lymph pathway for renal handling of lipoproteins. IsoLG-modified apoAI was not only a marker of renal injury but also directly damaged renal cells. IsoLG-apoAI increased inflammatory cytokines in cultured tubular epithelial cells (TECs), activated lymphatic endothelial cells (LECs), and caused greater contractility of renal lymphatic vessels than unmodified apoAI. In vivo, inhibition of IsoLG by a dicarbonyl scavenger reduced both albuminuria and urinary apoAI and decreased TEC and LEC injury, lymphangiogenesis, and interstitial fibrosis. Our results indicate that IsoLG-modified apoAI is, to our knowledge, a novel pathogenic mediator and therapeutic target in kidney disease.

Knockout of the Circadian Clock Protein PER1 (Period1) Exacerbates Hypertension and Increases Kidney Injury in Dahl Salt-Sensitive Rats.

Circadian rhythms play an essential role in physiological function. The molecular clock that underlies circadian physiological function consists of a core group of transcription factors, including the protein PER1 (Period1). Studies in mice show that PER1 plays a role in the regulation of blood pressure and renal sodium handling; however, the results are dependent on the strain being studied. Using male Dahl salt-sensitive (SS) rats with global knockout of PER1 (SSPer1-/-), we aim to test the hypothesis that PER1 plays a key role in the regulation of salt-sensitive blood pressure. The model was generated using CRISPR/Cas9 and was characterized using radiotelemetry and measures of renal function and circadian rhythm. SSPer1-/- rats had similar mean arterial pressure when fed a normal 0.4% NaCl diet but developed augmented hypertension after three weeks on a high-salt (4% NaCl) diet. Despite being maintained on a normal 12:12 light:dark cycle, SSPer1-/- rats exhibited desynchrony mean arterial pressure rhythms on a high-salt diet, as evidenced by increased variability in the time of peak mean arterial pressure. SSPer1-/- rats excrete less sodium after three weeks on the high-salt diet. Furthermore, SSPer1-/- rats exhibited decreased creatinine clearance, a measurement of renal function, as well as increased signs of kidney tissue damage. SSPer1-/- rats also exhibited higher plasma aldosterone levels. Altogether, our findings demonstrate that loss of PER1 in Dahl SS rats causes an array of deleterious effects, including exacerbation of the development of salt-sensitive hypertension and renal damage.

Mutagenesis of the cleavage site of (pro)renin receptor abrogates aldosterone-salt-induced hypertension and renal injury in mice.

Soluble (pro)renin receptor (sPRR), the extracellular domain of (pro)renin receptor (PRR), is primarily generated by site-1 protease and furin. It has been reported that sPRR functions as an important regulator of intrarenal renin contributing to angiotensin II (ANG II)-induced hypertension. Relatively, less is known for the function of sPRR in ANG II-independent hypertension such as mineralocorticoid excess. In the present study, we used a novel mouse model with mutagenesis of the cleavage site in PRR (termed as PRRR279V/L282V or mutant) to examine the phenotype during aldosterone (Aldo)-salt treatment. The hypertensive response of mutant mice to Aldo-salt treatment was blunted in parallel with the attenuated response of plasma volume expansion and renal medullary α-epithelial Na+ channel expression. Moreover, Aldo-salt-induced hypertrophy in the heart and kidney as well as proteinuria were improved, accompanied by blunted polydipsia and polyuria. Together, these results represent strong evidence favoring endogenous sPRR as a mediator of Aldo-salt-induced hypertension and renal injury.NEW & NOTEWORTHY We used a novel mouse model with mutagenesis of the cleavage site of PRR to support soluble PRR as an essential mediator of aldosterone-salt-induced hypertension and also as a potential therapeutic target for patients with mineralocorticoid excess. We firstly report that soluble PRR-dependent pathway medicates the Na+-retaining action of aldosterone in the distal nephron, which opens up a new area for a better understanding of the molecular basis of renal handling of Na+ balance and blood pressure.

Genetic deletion of the nuclear factor of activated T cells 5 in collecting duct principal cells causes nephrogenic diabetes insipidus.

Water homeostasis is tightly regulated by the kidneys via the process of urine concentration. During reduced water intake, the antidiuretic hormone arginine vasopressin (AVP) binds to the vasopressin receptor type II (V2R) in the kidney to enhance countercurrent multiplication and medullary osmolality, and increase water reabsorption via aquaporin-2 (AQP2) water channels. The importance of this AVP, V2R, and AQP2 axis is highlighted by low urine osmolality and polyuria in people with various water balance disorders, including nephrogenic diabetes insipidus (NDI). ELF5 and nuclear factor of activated T cells 5 (NFAT5) are two transcription factors proposed to regulate Aqp2 expression, but their role is poorly defined. Here we generated two novel mouse lines with principal cell (PC)-specific deletion of ELF5 or NFAT5 and phenotyped them in respect to renal water handling. ELF5-deficient mice (ELF5PC-KO ) had a very mild phenotype, with no clear differences in AQP2 abundance, and mild differences in renal water handling and maximal urinary concentrating capacity. In contrast, NFAT5 (NFAT5PC-KO ) mice had significantly higher water intake and their 24 h urine volume was almost 10-fold greater than controls. After challenging with dDAVP or 8h water restriction, NFAT5PC-KO mice were unable to concentrate their urine, demonstrating that they suffer from NDI. The abundance of AQP2, other AQPs, and the urea transporter UT-A1 were greatly decreased in NFAT5PC-KO mice. In conclusion, NFAT5 is a major regulator of not only Aqp2 gene transcription, but also other genes important for water homeostasis and its absence leads to the development of NDI.

Acute effect of empagliflozin on serum uric acid – a subanalysis of the EMPAG-HF trial (effects of empagliflozin on diuresis and renal function in patients with acute decompensated heart failure)

Abstract Background Elevated levels of uric acid (UA) have been associated with worsening of outcomes in cardiovascular and renal disease and may lead to gout. Patients with acute decompensated heart failure (ADHF) may develop hyperuricemia under intensified diuretic treatment. In this setting, the effect of empagliflozin on serum uric acid remains unknown. Aim/Purpose The aim of this subanalysis in patients with ADHF was to assess how additive treatment with empagliflozin influences the concentration of serum uric acid and potential related outcomes. Methods In the single-center, prospective, double-blind, placebo-controlled EMPAG-HF trial, patients with ADHF were screened and randomized within 12 hours following hospital admission to receive either empagliflozin 25 mg or placebo in addition to standard medical treatment over five days. Sixtypatients (mean age 74,7±9,9, 39% female) were enrolled and randomized 1:1 irrespective of left ventricular ejection fraction or the presence of diabetes. UA in serum was determined daily and renal handling of UA was evaluated by fractional excretion of UA (FEUA). Two-way mixed ANOVA and Wilcoxon rank-sum test were used for statistical analyses. Results The empagliflozin group comprised 30 patients and the placebo group comprised 29 patients. There were no differences in baseline patient characteristics including LVEF, NT-proBNP, eGFR, HbA1c. In the placebo group, UA increased from baseline 487.86±32.21 μmol/l to 500.38±28.37 μmol/l at day (d) 2 (p=0.045), 512.36±29.43 μmol/l at d3 (p=0.018), and 518.46±31.14 μmol/l at d4 (p=0.021). By contrast, in the empagliflozin group, UA tended to decrease compared to baseline and was significantly lower compared to placebo at d3 (436.08±23.94 vs. 512.36±29.43 μmol/l, p=0.049), d4 (423.20±24.12 vs. 518.46±31.14 μmol/l, p=0.018), and d5 (423.17±24.75 vs. 508.62±31.08 μmol/l, p=0.037). Serum UA returned to baseline levels in both groups 30 days after cessation of empagliflozin. The reduction of UA in the empagliflozin group was associated with a significant enhancement in FEUA (5.49±0.81% vs. 9.38±1.07%, p=0.004). Conclusion Our data suggest that the additive treatment with empagliflozin in patients with acute decompensated heart failure lowers the levels of serum uric acid compared to loop diuretics alone. This effect may be attributed to an improved renal elimination of UA and a better preservation of kidney function. It remains to be clarified whether this uricosuric effect of empagliflozin also contributes to its prognostic benefits in heart failure. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Department of Internal Medicine I, Division of Cardiology, Angiology and Intensive Medical Care, University Hospital Jena, Friedrich-Schiller-University, Jena, Germany) Boehringer Ingelheim Inc.

PTH and FGF23 exert interdependent effects on renal phosphate handling: evidence from patients with hypoparathyroidism and hyperphosphatemic familial tumoral calcinosis treated with synthetic human PTH 1-34

PTH and FGF23 exert interdependent effects on renal phosphate handling: evidence from patients with hypoparathyroidism and hyperphosphatemic familial tumoral calcinosis treated with synthetic human PTH 1-34

Association of TRPV5, CASR, and CALCR genetic variants with kidney stone disease susceptibility in Egyptians through main effects and gene–gene interactions

Kidney stone disease (KSD) represents an urgent medical problem because of increasing its prevalence. Several functional polymorphisms in genes involved in the renal handling of calcium were associated with KSD pathogenesis. Among those, the rs4236480 of transient receptor potential vanilloid member 5 (TRPV5) gene, the rs1801725 of calcium-sensing receptor (CASR) gene, and the rs1801197 of calcitonin receptor (CALCR) gene appear to be of great importance. Due to the scarce data on the Egyptians, this study aimed to evaluate the association of these candidate genetic variants with the risk of developing KSD in an Egyptian population. To do so, the biochemical parameters were measured along with the genotyping of the three polymorphisms using allelic discrimination assay in 134 KSD patients and 86 age and sex-matched healthy subjects. The results showed that the genotypic distributions and allelic frequencies of the studied variants were significantly different between cases and controls. The three polymorphisms increased the risk of KSD significantly under all the tested genetic models (OR ranges from 2.152 to 5.994), except for the recessive model of the CALCR rs1801197 polymorphism after Bonferroni correction. The gene–gene interaction analyzed by multifactor dimensionality reduction selected the three-locus combination as the best model associated with the susceptibility to KSD with OR 9.706. Further, synergistic interactions were identified between TRPV5 rs4236480 and CALCR rs1801197 variants and CASR rs1801725 and CALCR rs1801197 variants. In conclusion, the TRPV5 rs4236480, CASR rs1801725, and CALCR rs1801197 polymorphisms showed a significant association with the risk of KSD in the Egyptian population. Furthermore, their complex interactions might have an impact on the genetic susceptibility to develop KSD.

Abstract 096: Adrenal-specific KO Of The Circadian Clock Protein Bmal1 Alters Blood Pressure Rhythm

BMAL1 is a core circadian clock protein that regulates most physiological functions, including blood pressure (BP). Global BMAL1 knockout (KO) male mice exhibit reduced, non-dipping BP and loss of diurnal rhythm of renal sodium (Na) excretion. Although, BP and renal Na excretion rhythm remained intact in kidney-specific BMAL1 KO male mice. The adrenal gland synthesizes hormones which influence BP rhythm and renal electrolyte handling. The role of adrenal BMAL1 in the regulation of BP and renal function remains unknown. The goal was to test the hypothesis that adrenal BMAL1 is required for normal circadian rhythms of BP and renal Na excretion. Adrenal-specific aldosterone synthase Cre positive (AS)-BMAL1 KO male mice ( n =5) and littermate Cre negative, floxed control (CNTL) male mice ( n =6) underwent a telemetry study to measure BP. Cosinor analysis was performed to assess BP rhythms. During telemetry recordings, mice were placed in metabolic cages for 5 days on a normal salt diet. The latter 3 days, 12 h urine samples were collected before each light-dark Zeitgeber (6AM and 6PM/ Zeitgeber Time (ZT)0 and ZT12) to measure night/day patterns in renal Na excretion. Kidneys were collected from a separate cohort of mice ( n =7-8/genotype) at ZT0 and ZT12 for gene expression analysis of key Na transporters. No BMAL1-dependent changes in the 24 h averages for BP were observed. Cosinor analysis revealed significant differences in BP rhythm, however. The period (time taken for a full circadian cycle, ~24 h) was significantly shortened for BP in AS-BMAL1 KO mice vs. CNTL (23 h 31 vs 24 h 16, p =0.01). Acrophase (the time at which BP peaks) was shifted ~2 hours later in KO mice (KO ZT17 h 38 vs CNTL ZT15 h 45, p =0.002). The MESOR (midline estimating statistic of rhythm) of BP remained similar between groups (KO 133.5 mmHg vs CNTL 132.7 mmHg, p =0.904). Day/night Na excretion was not different in AS-BMAL1 KO mice vs. CNTL (ANOVA interaction p =0.168). This was consistent with a lack of genotype effects on gene expression for NCC, α, β, or γ ENaC. Significant time of day effects were observed for all 4 genes (all with p <0.001). In conclusion, BMAL1 KO in the adrenal gland altered BP rhythm, with no changes in renal Na excretion. This work is the first to investigate the role of adrenal BMAL1 on BP regulation.

Abstract 042: A Novel (pro)renin Receptor Variant Prr24 As A Specific Renin Receptor And Key Regulator Of Nkcc2 And Urine Concentrating Capability

(Pro)renin receptor (PRR) has emerged as a key regulator of renal handling of Na + and water, and blood pressure (BP). Renal action of PRR is at least in part mediated through its ability to activate tissue prorenin and renin. In preliminary studies, investigation of a “non-specific” protein band recognized by an anti-PRR antibody against the extracellular domain led to identification of a novel 24-kDa isoform of PRR, termed as PRR24. PRR24 was encoded by a novel cDNA with part of 5’UTR arising from retention of intron 3 and an ATG in exon 5 as an alternative start codon so that this isoform overlaps completely with PRR except that N-terminal 136 amino acids are missing. PRR24 selectively bound and activated renin but not prorenin whereas PRR non-selectively interacted both prorenin and renin. PRR24 protein and mRNA expression was exclusively detected in the renal medulla but not renal cortex or extrarenal organs. Within the kidney, PRR24 mRNA was restricted to medullary thick ascending limb (mTAL) as assessed by RT-PCR on microdissected nephron segments. Using CRISP/Cas9 strategy, we generated a mouse model with mutagenesis of the start codon in exon 5 (termed PRR24 mut ) by replacing methionine with glutamine in PRR. Renal medullary protein expression of PRR24 was barely detectable contrasting unchanged PRR abundance in the null mice. PRR24 mut mice was born at Mendelian ratio and didn’t exhibit developmental abnormalities or mortality as seen in systemic PRR KO mice. PRR24 mut mice developed polyuria, hypoosmotic urine, polydipsia, hypotension (radiotelemetry MAP: WT 120 + 0.8 vs. Mutant 112 + 1.4 mmHg; p<0.05). Plasma volume assessed indirectly by hematocrit and directly assessed by using a fluorescent tracer was consistently reduced by 5-10%. Renal expression of NKCC2 was downregulated by 70% in parallel with reduced diuretic response to furosemide. Following 24-h water deprivation, the upregulation of NKCC2 expression was blunted in PRR24 mut mice associated with impaired urine concentrating capability as assessed by urine volume and osmolality. Overall, PRR24 is a novel PRR variant and serves as a specific renin receptor to regulate renal NKCC2 expression to ultimately determine urine concentrating capability.

Abstract 031: Mutagenesis Of The Cleavage Site Of (pro)renin Receptor Abrogates Aldosterone-salt-induced Hypertension And Renal Injury In Mice

Soluble (pro)renin receptor (sPRR), the extracellular domain of (pro)renin receptor (PRR), is primarily generated by site-1 protease (S1P) and furin. It has been reported that sPRR functions as an important regulator of intrarenal renin contributing to angiotensin II (Ang II)-induced hypertension. Relatively, less is known for the function of sPRR in Ang II-independent hypertension such as mineralocorticoid excess. In the present study, we employed a novel mouse model with mutagenesis of the cleavage site in PRR (termed as Mutant mice) to examine the phenotype during aldosterone (Aldo)-salt treatment. The hypertensive response of Mutant mice to Aldo-salt treatment was blunted (day 12, delta MAP: WT/Aldo-salt 22.4±4.1 mm Hg vs. Mutant/Aldo-salt 11.7±2.5 mm Hg, n=6, p<0.05), in parallel with attenuated response of plasma volume expansion and sodium-water retention. Renal cortical and inner medullary mRNA and protein expression of α-, β-, and γ-subunits of epithelial sodium channel (ENaC) were all increased in WT mice after Aldo-salt treatment but only the increase of α-ENaC in inner medulla was blunted in Mutant mice. The plasma sPRR was increased 1.5-fold after Aldo-salt treatment, which was reduced by 57% in Mutant mice. Moreover, Aldo-salt-induced hypertrophy in the heart and kidney, which were improved in Mutant mice (Heart Weight/Body Weight: WT/Aldo-salt 5.8±0.4 mg/g vs. Mutant/Aldo-salt 4.2±0.3 mg/g; Kidney Weight/Body Weight: WT/Aldo-salt 9.9±0.4 mg/g vs. Mutant/Aldo-salt 7.3±0.4 mg/g, n=6, p<0.01), accompanied with blunted polydipsia and polyuria in Mutant mice. Furthermore, the urinary albumin was increased 8.3-fold after Aldo-salt treatment, which was reduced by 32% in Mutant mice. The mRNA levels of Fibronectin, α-SMA, IL-6, MCP-1 and TGF-β were increased in Aldo-salt/WT mice, which were prevented almost 60% in Aldo-salt/Mutant mice. Together, these results represent strong evidence favoring endogenous sPRR as a mediator of Aldo-salt-induced hypertension and renal injury. Here, we firstly report that sPRR-dependent pathway medicates the Na + -retaining action of Aldo in the distal nephron, which opens up a new area for a better understanding of the molecular basis of renal handling of Na + balance and blood pressure.

215.12: Renal Handling of Phosphorus Very Early After Kidney Transplantation in Adults

Introduction: To our knowledge there are no studies that describe phosphorus behavior in the early days of post kidney and simultaneous kidney-pancreas transplant. We aim to describe the urinary handling of phosphorus as well as the bone and mineral metabolism immediately before and during the first 8 days of post transplantation. Methods: Observational descriptive longitudinal study including 61 renal and simultaneous kidney-pancreas transplant adult recipients (either living or deceased donors) at Hospital CEMIC Buenos Aires. Baseline blood samples were drawn pre transplant and then after surgery along with urine samples at days 1,3,5, and 7 to measure serum phosphorus, calcium, creatinine, pre-transplant intact parathormone (iPTH), urinary phosphorus and creatinine excretion, glomerular filtration rate (by urinary creatinine clearance), and fractional excretion of phosphorus. Results: Mean age was 49 ± 13, 54% were male, 90% were kidney transplants, 75% received organs from deceased donors, average serum vitamin D was 22.1 ng/mL, 37% had hyperparathyroidism (iPTH>580 pg/mL) and 13% had hypoparathyroidism (iPTH<120 pg/mL) before transplant. We observed that creatininemia decreased (5.9 mg/dL at day 1 and 2.0 mg/dL at day 7 p 0.0001) and also serum phosphorus decreased (6.2 ± 1.9 mg/dL at day 1 and 4.2 ± 2.8 mg/dL at day 7 p 0.0001), while serum calcium and phosphaturia increased [0.5 g/day (0.1-1.3) at day 1 vs 0.63 g/day (0.4-0.88) at day 7 p 0,015] during the follow up. Interestingly, there were no changes in phosphorus fractional excretion (PEF) (table 1). In subgroup analysis recipients of living donors showed lower phosphatemia (4.8 mg/dL vs 6.7 mg/dL at day 1, p 0.000, and 2,2 mg/dL vs 4.8 mg/dL at day 7, p 0.000) probably related to the greater GFR and substantially higher phosphaturia [1.44 g/day (0.81-1.69) vs 0.29 (0.8-0.76) at day 1, p 0.000], on the other hand, PEF was lower when compared to deceased donors recipients (DDR). Among DDR (n:46), those without delayed graft function (n:29) (DGF) had higher GFR and phosphaturia during the whole study, [a greater phosphorus excretion was statistically significant at day 1 and 3: 0.54 g/day vs 0.10 g/day p 0.000 at day 1, 0.85 g/day vs 0.10 g/day at day 3, 0.77 g/day vs 0.47 g/day p 0.09 at day 5, 0.71 g/day vs 0.42 g/day p 0.07 at day 7 (table 2)], and there was no difference regarding PEF compared to those with DGF. Patients were divided by tertiles of iPTH, and there were no differences in any measured aspect and also no correlation between iPTH and phosphaturia. Conclusion: In this study we observed how phosphaturia improves with the recovery of GFR while PEF remains unchanged. This finding suggests that the tubules and interstitium, together with the hormonal context might not play a significant role in phosphorus handling at this point when the organ is still regaining function.

Mineralocorticoid Receptor Activation in Vascular Insulin Resistance and Dysfunction.

Systemic insulin resistance is characterized by reduced insulin metabolic signaling and glucose intolerance. Mineralocorticoid receptors (MRs), the principal receptors for the hormone aldosterone, play an important role in regulating renal sodium handling and blood pressure. Recent studies suggest that MRs also exist in tissues outside the kidney, including vascular endothelial cells, smooth muscle cells, fibroblasts, perivascular adipose tissue, and immune cells. Risk factors, including excessive salt intake/salt sensitivity, hypertension, and obesity, can lead to the activation of vascular MRs to promote inflammation, oxidative stress, remodeling, and fibrosis, as well as cardiovascular stiffening and microcirculatory impairment. These pathophysiological changes are associated with a diminished ability of insulin to initiate appropriate intracellular signaling events, resulting in a reduced glucose uptake within the microcirculation and related vascular insulin resistance. Therefore, the pharmacological inhibition of MR activation provides a potential therapeutic option for improving vascular function, glucose uptake, and vascular insulin sensitivity. This review highlights recent experimental and clinical data that support the contribution of abnormal MR activation to the development of vascular insulin resistance and dysfunction.

Sex Differences in Diurnal Sodium Handling During Diet-Induced Obesity in Rats.

Emerging evidence over the past several years suggests that diurnal control of sodium excretion is sex dependent and involves the renal endothelin system. Given recent awareness of disruptions of circadian function in obesity, we determined whether diet-induced obesity impairs renal handling of an acute salt load at different times of day and whether this varies by sex and is associated with renal endothelin dysfunction. Male and female Sprague-Dawley rats were placed on a high-fat diet for 8 weeks before assessing renal sodium handling and blood pressure. Male, but not female, rats on high fat had a significantly reduced natriuretic response to acute NaCl injection at the beginning of their active period that was associated with lower endothelin 1 (ET-1) excretion, lower ET-1 mRNA expression in the cortex and outer medulla as well as lower ETB receptor expression in the outer medulla of the high-fat rats. Obese males also had significantly higher blood pressure (telemetry) that was exacerbated by adding high salt to the diet during the last 2 weeks. While female rats developed hypertension with a high-fat diet, they were not salt sensitive and ET-1 excretion was unchanged. These data identify diet-induced obesity as a sex-specific disruptive factor for maintaining proper sodium handling. Although high-fat diets induce hypertension in both sexes, these data reveal that males are at greater risk of salt-dependent hypertension and further suggest that females have more redundant systems that can be productive against salt-sensitive hypertension in at least some circumstances.

Hypomagnesemia, Hypocalcemia, and Tubulointerstitial Nephropathy Caused by Claudin-16 Autoantibodies.

Chronic hypomagnesemia is commonly due to diarrhea, alcoholism, and drugs. More rarely, it is caused by genetic defects in the effectors of renal magnesium reabsorption. In an adult patient with acquired severe hypomagnesemia, hypocalcemia, tubulointerstitial nephropathy, and rapidly progressing kidney injury, similarities between the patient's presentation and features of genetic disorders of renal magnesium transport prompted us to investigate whether the patient had an acquired autoimmune cause of renal magnesium wasting. To determine if the patient's condition might be explained by autoantibodies directed against claudin-16 or claudin-19, transmembrane paracellular proteins involved in renal magnesium absorption, we conducted experiments with claudin knockout mice and transfected mouse kidney cells expressing human claudin-16 or claudin-19. We also examined effects on renal magnesium handling in rats given intravenous injections of IgG purified from sera from the patient or controls. Experiments with the knockout mice and in vitro transfected cells demonstrated that hypomagnesemia in the patient was causally linked to autoantibodies directed against claudin-16, which controls paracellular magnesium reabsorption in the thick ascending limb of Henle's loop. Intravenous injection of IgG purified from the patient's serum induced a marked urinary waste of magnesium in rats. Immunosuppressive treatment combining plasma exchange and rituximab was associated with improvement in the patient's GFR, but hypomagnesemia persisted. The patient was subsequently diagnosed with a renal carcinoma that expressed a high level of claudin-16 mRNA. Pathogenic claudin-16 autoantibodies represent a novel autoimmune cause of specific renal tubular transport disturbances and tubulointerstitial nephropathy. Screening for autoantibodies targeting claudin-16, and potentially other magnesium transporters or channels in the kidney, may be warranted in patients with acquired unexplained hypomagnesemia.

Revisiting the relationship between (Pro)Renin receptor and the intrarenal RAS: focus on the soluble receptor.

The (pro)renin receptor (PRR), also termed as ATPase H+ transporting accessory protein 2 (ATP6AP2), was originally cloned as a specific receptor for prorenin and renin [together called (pro)renin]. Given the wide tissue distribution of PRR, PRR was further postulated to act as a regulator of tissue renin. However, assigning a physiological role of PRR within the renin-angiotensin system (RAS) has been challenging largely due to its pleotropic functions in regulation of embryogenesis, autophagy, and H+ transport. The current review will summarize recent advances in understanding the roles of sPPR within the intrarenal RAS as well as those outside this local system. Site-1 protease (S1P) is a predominant source of sPPR at least in the kidney. So far most of the known physiological functions of PRR including renal handling of electrolytes and fluid and blood pressure are mediated by sPRR. In particular, sPRR serves as a positive regulator of collecting duct renin to activate the intrarenal RAS during water deprivation or angiotensin-II (AngII) infusion. However, PRR/sPRR can act in renin-independent manner under other circumstances. S1P-derived sPRR has emerged as a key regulator of kidney function and blood pressure and its relationship with the intrarenal RAS depends on the physiological context.

Are polymorphisms affecting serum urate, renal urate handling and alcohol intake associated with co-morbidities in gout cases? A case–control study using data from the UK Biobank

To examine the association between common comorbidities, eGFR and loci involved in the hyperuricaemia-gout transition. This study was conducted in people with gout from the UK Biobank. Logistic regression was used to examine the association between self-reported physician-diagnosed hypertension, diabetes, hypercholesterolemia and ischaemic heart disease (IHD) with the following variants: rs1260326(GCKR), rs16890979(SLC2A9), rs2231142(ABCG2), rs1229984(ADH1B) and rs2078267(SLC22A11) and adjusted for age, sex and 10-principal components. Linear regression was used to examine the association with eGFR. 7,049 participants with gout were included. After adjusting for multiple testing, there was a statistically significant positive association between urate lowering allele at SLC2A9 and hypertension, and negative association between urate raising allele at ABCG2 and hypertension (OR 1.17 and OR 0.86, respectively). Number of urate lowering risk alleles associated with hypertension [OR (95%CI) 1.13 (1.06–1.21)]. High eGFR associated with urate raising allele at rs2231142 (β = 1.38). The SNP in ADH1B that protects from alcohol excess showed a negative association with IHD (OR 0.53). Unlike in general population studies urate lowering genetic variants associate with hypertension in gout patients with dose–response. This may be due to high prevalence of other risk factors of hypertension such as obesity, poor diet etc. and needs validation in independent datasets.

Plasma Levels and Renal Handling of Amino Acids Contribute to Determination of Risk of Mortality or Feed of Ventilation in Patients with COVID-19.

COVID-19 infection may lead to serious complications, e.g., need for mechanical ventilation or death in some cases. A retrospective analysis of patients referred to our COVID Emergency Department, indiscriminately, was performed. A routine lab analysis measured amino acids in plasma and urine of patients. Data of surviving and deceased patients and those requiring or not requiring mechanical ventilation were compared, and logistic regression analyses have been performed. Deceased patients were older, had higher blood glucose, potassium, AST, LDH, troponin, d-dimer, hsCRP, procalcitonin, interleukin-6 levels (p < 0.05 for all). They had lower plasma serine, glycine, threonine, tryptophan levels (p < 0.01), higher tyrosine and phenylalanine levels (p < 0.05), and higher fractional excretion of arginine, methionine, and proline (p < 0.05) than survivors. In a regression model, age, severity score of COVID-pneumonia, plasma levels of threonine and phenylalanine were predictors of in-hospital mortality. There was a difference in ventilated vs. non-ventilated patients in CT-scores, glucose, and renal function (p < 0.001). Using logistic regression, CT-score, troponin, plasma level, and fractional excretion of glycine were predictors of ventilation. Plasma levels and renal excretion of certain amino acids are associated with the outcome of COVID-19 infection beside other parameters such as the CT-score or age.

Empagliflozin Treatment Attenuates Hepatic Steatosis by Promoting White Adipose Expansion in Obese TallyHo Mice.

Sodium-glucose co-transporters (SGLTs) serve to reabsorb glucose in the kidney. Recently, these transporters, mainly SGLT2, have emerged as new therapeutic targets for patients with diabetes and kidney disease; by inhibiting glucose reabsorption, they promote glycosuria, weight loss, and improve glucose tolerance. They have also been linked to cardiac protection and mitigation of liver injury. However, to date, the mechanism(s) by which SGLT2 inhibition promotes systemic improvements is not fully appreciated. Using an obese TallyHo mouse model which recapitulates the human condition of diabetes and nonalcoholic fatty liver disease (NAFLD), we sought to determine how modulation of renal glucose handling impacts liver structure and function. Apart from an attenuation of hyperglycemia, Empagliflozin was found to decrease circulating triglycerides and lipid accumulation in the liver in male TallyHo mice. This correlated with lowered hepatic cholesterol esters. Using in vivo MRI analysis, we further determined that the reduction in hepatic steatosis in male TallyHo mice was associated with an increase in nuchal white fat indicative of “healthy adipose expansion”. Notably, this whitening of the adipose came at the expense of brown adipose tissue. Collectively, these data indicate that the modulation of renal glucose handling has systemic effects and may be useful as a treatment option for NAFLD and steatohepatitis.