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The nephron is the functional unit of the kidney involved in the critical interplay of fluid and electrolyte homeostasis by glomerular filtration, selective tubular reabsorption, and secretion. This article will discuss the structure and function of each segment of the nephron, and the physiology pertaining to the formation of urine. [ABSTRACT FROM AUTHOR]

Resumen: Las enfermedades renales que cursan con hipomagnesemia son un grupo complejo y variopinto de tubulopatías producidas por mutaciones en genes que codifican proteínas que se expresan en la rama gruesa ascendente del asa de Henle y en el túbulo contorneado distal. En el presente artículo revisamos la descripción inicial, la expresividad clínica y la etiología de cuatro de las primeras causas de tubulopatías hipomagnesémicas que se describieron: las enfermedades de Bartter tipo 3 y Gitelman, la hipomagnesemia con hipocalcemia secundaria autosómica recesiva y la hipomagnesemia familiar con hipercalciuria y nefrocalcinosis. A continuación, se describen los patrones bioquímicos básicos que se observan en las hipomagnesemias tubulares renales y las modalidades de transporte e interacción que concurren entre los transportadores implicados en la reabsorción de magnesio en el túbulo contorneado distal. Finalmente, se comunica la reciente descripción de una nueva tubulopatía hipomagnesémica, la hipomagnesemia con hipocalcemia secundaria tipo 2 causada por una reducción de la actividad del canal TRPM7. Abstract: Renal diseases associated with hypomagnesemia are a complex and diverse group of tubulopathies caused by mutations in genes encoding proteins that are expressed in the thick ascending limb of the loop of Henle and in the distal convoluted tubule. In this paper, we review the initial description, the clinical expressiveness and etiology of four of the first hypomagnesemic tubulopathies described: Type 3 Bartter and Gitelman diseases, Autosomal recessive hypomagnesemia with secondary hypocalcemia and Familial hypomagnesemia with hypercalciuria and nephrocalcinosis. The basic biochemical patterns observed in renal tubular hypomagnesemias and the modalities of transport and interaction that occur between the transporters involved in the reabsorption of magnesium in the distal convoluted tubule are described below. Finally, the recent report of a new renal disease with hypomagnesemia, Type 2 hypomagnesemia with secondary hypocalcemia caused by reduced TRPM7 channel activity is described.

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The paired kidneys play a significant role in the human body due to the multitude of physiological tasks. Complex biochemical processes keep the sensitive electrolyte and water balance stable and thus ensure the organism's ability to adapt to exogenous and endogenous factors, which is essential for survival. The drug class of diuretics includes substances with very differing pharmacological characteristics. The functioning of the nephron is therefore indispensable for a deeper understanding of the pharmacodynamics, pharmacokinetics and side effect profile of diuretics. In the treatment of acute heart failure with pulmonary congestion, certain diuretics represent an important therapeutic option to counteract hypervolemia and thus an increase in preload. According to current data, diuretics have no proven benefits in the treatment or prevention of acute kidney injury but they can counteract hypervolemia and under certain conditions even reduce the use of renal replacement procedures. [ABSTRACT FROM AUTHOR]

The exclusive expression of uromodulin in the kidneys has made it an intriguing protein in kidney and cardiovascular research. Genome-wide association studies discovered variants of uromodulin that are associated with chronic kidney diseases and hypertension. Urinary and circulating uromodulin levels reflect kidney and cardiovascular health as well as overall mortality. More recently, Mendelian randomization studies have shown that genetically driven levels of uromodulin have a causal and adverse effect on kidney function. On a mechanistic level, salt sensitivity is an important factor in the pathophysiology of hypertension, and uromodulin is involved in salt reabsorption via the NKCC2 (Na+-K+-2Cl- cotransporter) on epithelial cells of the ascending limb of loop of Henle. In this review, we provide an overview of the multifaceted physiology and pathophysiology of uromodulin including recent advances in its genetics; cellular trafficking; and mechanistic and clinical studies undertaken to understand the complex relationship between uromodulin, blood pressure, and kidney function. We focus on tubular sodium reabsorption as one of the best understood and pathophysiologically and clinically most important roles of uromodulin, which can lead to therapeutic interventions. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is associated with morbidity and mortality. Urinary biomarkers may disentangle its clinical heterogeneity. Olfactomedin 4 (OLFM4) is a secreted glycoprotein expressed in stressed neutrophils and epithelial cells. In septic mice, OLFM4 expression localized to the kidney's loop of Henle (LOH) and was detectable in the urine. We hypothesized that urine OLFM4 (uOLFM4) will be increased in patients with AKI and sepsis. Urine from critically ill pediatric patients was obtained from a prospective study based on AKI and sepsis status. uOLFM4 was quantified with a Luminex immunoassay. AKI was defined by KDIGO severe criteria. Sepsis status was extracted from the medical record based on admission diagnosis. Immunofluorescence on pediatric kidney biopsies was performed with NKCC2, uromodulin and OLFM4 specific antibodies. Eight patients had no sepsis, no AKI; 7 had no sepsis but did have AKI; 10 had sepsis, no AKI; 11 had sepsis and AKI. Patients with AKI had increased uOLFM4 compared to no/stage 1 AKI (p = 0.044). Those with sepsis had increased uOLFM4 compared to no sepsis (p = 0.026). uOLFM4 and NGAL were correlated (r2 0.59, 95% CI 0.304–0.773, p = 0.002), but some patients had high uOLFM4 and low NGAL, and vice versa. Immunofluorescence on kidney biopsies demonstrated OLFM4 colocalization with NKCC2 and uromodulin, suggesting expression in the thick ascending LOH (TALH). We conclude that AKI and sepsis are associated with increased uOLFM4. uOLFM4 and NGAL correlated in many patients, but was poor in others, suggesting these markers may differentiate AKI subgroups. Given OLFM4 colocalization to human TALH, we propose OLFM4 may be a LOH‐specific AKI biomarker. [ABSTRACT FROM AUTHOR]

Abstract Acute kidney injury (AKI) is associated with morbidity and mortality. Urinary biomarkers may disentangle its clinical heterogeneity. Olfactomedin 4 (OLFM4) is a secreted glycoprotein expressed in stressed neutrophils and epithelial cells. In septic mice, OLFM4 expression localized to the kidney's loop of Henle (LOH) and was detectable in the urine. We hypothesized that urine OLFM4 (uOLFM4) will be increased in patients with AKI and sepsis. Urine from critically ill pediatric patients was obtained from a prospective study based on AKI and sepsis status. uOLFM4 was quantified with a Luminex immunoassay. AKI was defined by KDIGO severe criteria. Sepsis status was extracted from the medical record based on admission diagnosis. Immunofluorescence on pediatric kidney biopsies was performed with NKCC2, uromodulin and OLFM4 specific antibodies. Eight patients had no sepsis, no AKI; 7 had no sepsis but did have AKI; 10 had sepsis, no AKI; 11 had sepsis and AKI. Patients with AKI had increased uOLFM4 compared to no/stage 1 AKI (p = 0.044). Those with sepsis had increased uOLFM4 compared to no sepsis (p = 0.026). uOLFM4 and NGAL were correlated (r2 0.59, 95% CI 0.304–0.773, p = 0.002), but some patients had high uOLFM4 and low NGAL, and vice versa. Immunofluorescence on kidney biopsies demonstrated OLFM4 colocalization with NKCC2 and uromodulin, suggesting expression in the thick ascending LOH (TALH). We conclude that AKI and sepsis are associated with increased uOLFM4. uOLFM4 and NGAL correlated in many patients, but was poor in others, suggesting these markers may differentiate AKI subgroups. Given OLFM4 colocalization to human TALH, we propose OLFM4 may be a LOH‐specific AKI biomarker.

Uromodulin, a urinary protein synthesized and secreted from the thick ascending limb (TAL) of the loop of Henle, is associated with hypertension through the activation of sodium reabsorption in the TAL. Uromodulin is a potential target for hypertension treatment via natriuresis. However, its biological function in epithelial cells of the distal nephron segment, particularly the collecting duct, remains unknown. Herein, we examined the regulation of uromodulin production during water deprivation in vivo as well as the effect of uromodulin on the activity of the water channel aquaporin−2 (AQP2) in vitro and in vivo using transgenic mice. Water deprivation upregulated uromodulin production; immunofluorescence experiments revealed uromodulin adhesion on the apical surface of the collecting duct. Furthermore, the activation of AQP2 was attenuated in mice lacking uromodulin. Uromodulin enhanced the phosphorylation and apical trafficking of AQP2 in mouse collecting duct cells treated with the vasopressin analog dDAVP. The uromodulin-induced apical trafficking of AQP2 was attenuated via endocytosis inhibitor treatment, suggesting that uromodulin activates AQP2 through the suppression of endocytosis. This study provides novel insights into the cross−talk between TAL and the collecting duct, and indicates that the modulation of uromodulin is a promising approach for diuresis and hypertension treatment. [ABSTRACT FROM AUTHOR]

The nephron is the functional unit of the kidney involved in the critical interplay of fluid and electrolyte homeostasis by glomerular filtration, selective tubular reabsorption and secretion. This article will discuss the structure and function of each segment of the nephron, and the physiology pertaining to the formation of urine. [ABSTRACT FROM AUTHOR]

Uromodulin, a urinary protein synthesized and secreted from the thick ascending limb (TAL) of the loop of Henle, is associated with hypertension through the activation of sodium reabsorption in the TAL. Uromodulin is a potential target for hypertension treatment via natriuresis. However, its biological function in epithelial cells of the distal nephron segment, particularly the collecting duct, remains unknown. Herein, we examined the regulation of uromodulin production during water deprivation in vivo as well as the effect of uromodulin on the activity of the water channel aquaporin−2 (AQP2) in vitro and in vivo using transgenic mice. Water deprivation upregulated uromodulin production; immunofluorescence experiments revealed uromodulin adhesion on the apical surface of the collecting duct. Furthermore, the activation of AQP2 was attenuated in mice lacking uromodulin. Uromodulin enhanced the phosphorylation and apical trafficking of AQP2 in mouse collecting duct cells treated with the vasopressin analog dDAVP. The uromodulin-induced apical trafficking of AQP2 was attenuated via endocytosis inhibitor treatment, suggesting that uromodulin activates AQP2 through the suppression of endocytosis. This study provides novel insights into the cross−talk between TAL and the collecting duct, and indicates that the modulation of uromodulin is a promising approach for diuresis and hypertension treatment.

Na+–K+–Cl− cotransporter 2 (NKCC2; SLC12A1) is an integral membrane protein that comes as three splice variants and mediates the cotranslocation of Na+, K+, and Cl− ions through the apical membrane of the thick ascending loop of Henle (TALH). In doing so, and through the involvement of other ion transport systems, it allows this nephron segment to reclaim a large fraction of the ultrafiltered Na+, Cl−, Ca2+, Mg2+, and HCO3− loads. The functional relevance of NKCC2 in human is illustrated by the many abnormalities that result from the inactivation of this transport system through the use of loop diuretics or in the setting of inherited disorders. The following presentation aims at discussing the physiological roles and molecular characteristics of Na+–K+–Cl− cotransport in the TALH and those of the individual NKCC2 splice variants more specifically. Many of the historical and recent data that have emerged from the experiments conducted will be outlined and their larger meaning will also be placed into perspective with the aid of various hypotheses. [ABSTRACT FROM AUTHOR]

Organoid technology is rapidly gaining ground for studies on organ (patho)physiology. Tubuloids are long-term expanding organoids grown from adult kidney tissue or urine. The progenitor state of expanding tubuloids comes at the expense of differentiation. Here, we differentiate tubuloids to model the distal nephron and collecting ducts, essential functional parts of the kidney. Differentiation suppresses progenitor traits and upregulates genes required for function. A single-cell atlas reveals that differentiation predominantly generates thick ascending limb and principal cells. Differentiated human tubuloids express luminal NKCC2 and ENaC capable of diuretic-inhibitable electrolyte uptake and enable disease modeling as demonstrated by a lithium-induced tubulopathy model. Lithium causes hallmark AQP2 loss, induces proliferation, and upregulates inflammatory mediators, as seen in vivo. Lithium also suppresses electrolyte transport in multiple segments. In conclusion, this tubuloid model enables modeling of the human distal nephron and collecting duct in health and disease and provides opportunities to develop improved therapies. [Display omitted] • Human tubuloid differentiation introduces distal nephron and collecting duct cells • Differentiated tubuloids demonstrate electrolyte reabsorption, a key renal function • A single-cell atlas shows differentiated tubuloid cells resemble in vivo equivalents • Differentiated tubuloids enable modeling of human lithium tubulopathy in vitro Tubuloid differentiation introduces distal nephron and collecting duct cell types that resemble their counterparts in human in vivo kidney tissue. Differentiated tubuloids demonstrate electrolyte reabsorption, a key renal function, and enable modeling of diseases of the human distal nephron and collecting duct in vitro. [ABSTRACT FROM AUTHOR]

BackgroundThe 2P domain potassium (K2P) channels are a recently discovered ion channel superfamily. Structurally, K2P channels are distinguished by the presence of two pore forming loops within one channel subunit. Functionally, they are characterized by their ability to pass potassium across the physiologic voltage range. Thus, K2P channels are also called open rectifier, background, or leak potassium channels. Patch clamp studies of renal tubules have described several open rectifier potassium channels that have as yet eluded molecular identification. We sought to determine the segment-specific expression of transcripts for the 14 known K2P channel genes in human nephron to identify potential correlates of native leak channels.MethodsHuman kidney samples were obtained from surgical cases and specific nephron segments were dissected. RNA was extracted and used as template for the generation of cDNA libraries. Real-time polymerase chain reaction (PCR) (TaqMan) was used to analyze gene expression.ResultsWe found significant (P < 0.05) expression of K2P10 in glomerulus, K2P5 in proximal tubule and K2P1 in cortical thick ascending limb of Henle's loop (cTAL) and in distal nephron segments. In addition, we repeatedly detected message for several other K2P channels with less abundance, including K2P3 and K2P6 in glomerulus, K2P10 in proximal tubule, K2P5 in thick ascending limb of Henle's loop, and K2P3, K2P5, and K2P13 in distal nephron segments.ConclusionK2P channels are expressed in specific segments of human kidney. These results provide a step toward assigning K2P channels to previously described native renal leaks.

Renal diseases associated with hypomagnesemia are a complex and diverse group of tubulopathies caused by mutations in genes encoding proteins that are expressed in the thick ascending limb of the loop of Henle and in the distal convoluted tubule. In this paper, we review the initial description, the clinical expressiveness and etiology of four of the first hypomagnesemic tubulopathies described: type 3 Bartter and Gitelman diseases, Autosomal recessive hypomagnesemia with secondary hypocalcemia and Familial hypomagnesemia with hypercalciuria and nephrocalcinosis. The basic biochemical patterns observed in renal tubular hypomagnesemias and the modalities of transport and interaction that occur between the transporters involved in the reabsorption of magnesium in the distal convoluted tubule are described below. Finally, the recent report of a new renal disease with hypomagnesemia, type 2 hypomagnesemia with secondary hypocalcemia caused by reduced TRPM7 channel activity is described., (Copyright © 2024. Published by Elsevier España, S.L.U.)

Claudins are a family of tight junction proteins that provide size and charge selectivity to solutes traversing the paracellular space. Thick ascending limbs (TALs) express numerous claudins, including claudin-19. Nitric oxide (NO), via cGMP, reduces dilution potentials in perfused TALs, a measure of paracellular permeability, but the role of claudin-19 is unknown. We hypothesized that claudin-19 mediates the effects of NO/cGMP on the paracellular pathway in TALs via increases in plasma membrane expression of this protein. We measured the effect of the NO donor spermine NONOate (SPM) on dilution potentials with and without blocking antibodies and plasma membrane expression of claudin-19. During the control period, the dilution potential was −18.2 ± 1.8 mV. After treatment with 200 μmol/l SPM, it was −14.7 ± 2.0 mV (P < 0.04). In the presence of claudin-19 antibody, the dilution potential was −12.7 ± 2.1 mV. After SPM, it was −12.9 ± 2.4 mV, not significantly different. Claudin-19 antibody alone had no effect on dilution potentials. In the presence of Tamm-Horsfall protein antibody, SPM reduced the dilution potential from −9.7 ± 1.0 to −6.3 ± 1.1 mV (P < 0.006). Dibutyryl-cGMP (500 µmol/l) reduced the dilution potential from −19.6 ± 2.6 to −17.2 ± 2.3 mV (P < 0.002). Dibutyryl-cGMP increased expression of claudin-19 in the plasma membrane from 29.9 ± 3.8% to 65.9 ± 10.1% of total (P < 0.011) but did not change total expression. We conclude that claudin-19 mediates the effects of the NO/cGMP signaling cascade on the paracellular pathway. [ABSTRACT FROM AUTHOR]

Calcium phosphate (CaP) crystals, which begin to form in the early segments of the loop of Henle (LOH), are known to act as precursors for calcium stone formation. The proximal tubule (PT), which is just upstream of the LOH and is a major site for Ca2+ reabsorption, could be a regulator of such CaP crystal formation. However, PT Ca2+ reabsorption is mostly described as being paracellular. Here, we show the existence of a regulated transcellular Ca2+ entry pathway in luminal membrane PT cells induced by Ca2+-sensing receptor (CSR, also known as CASR)-mediated activation of transient receptor potential canonical 3 (TRPC3) channels. In support of this idea, we found that both CSR and TRPC3 are physically and functionally coupled at the luminal membrane of PT cells. More importantly, TRPC3-deficient mice presented with a deficiency in PT Ca2+ entry/transport, elevated urinary [Ca2+], microcalcifications in LOH and urine microcrystals formations. Taken together, these data suggest that a signaling complex comprising CSR and TRPC3 exists in the PT and can mediate transcellular Ca2+ transport, which could be critical in maintaining the PT luminal [Ca2+] to mitigate formation of the CaP crystals in LOH and subsequent formation of calcium stones. [ABSTRACT FROM AUTHOR]

Twin and genealogy studies suggest a strong genetic component of nephrolithiasis. Likewise, urinary traits associated with renal stone formation were found to be highly heritable, even after adjustment for demographic, anthropometric and dietary covariates. Recent high-throughput sequencing projects of phenotypically well-defined cohorts of stone formers and large genome-wide association studies led to the discovery of many new genes associated with kidney stones. The spectrum ranges from infrequent but highly penetrant variants (mutations) causing mendelian forms of nephrolithiasis (monogenic traits) to common but phenotypically mild variants associated with nephrolithiasis (polygenic traits). About two-thirds of the genes currently known to be associated with nephrolithiasis code for membrane proteins or enzymes involved in renal tubular transport. The thick ascending limb of Henle and connecting tubules are of paramount importance for renal water and electrolyte handling, urinary concentration and maintenance of acid-base homeostasis. In most instances, pathogenic variants in genes involved in thick ascending limb of Henle and connecting tubule function result in phenotypically severe disease, frequently accompanied by nephrocalcinosis with progressive CKD and to a variable degree by nephrolithiasis. The aim of this article is to review the current knowledge on kidney stone disease associated with inherited defects in the thick ascending loop of Henle and the connecting tubules. We also highlight recent advances in the field of kidney stone genetics that have implications beyond rare disease, offering new insights into the most common type of kidney stone disease, i.e., idiopathic calcium stone disease. [ABSTRACT FROM AUTHOR]

In temperate countries, heat recovery is often desirable through mechanical ventilation with heat recovery (MVHR). Drawbacks of MVHR include use of electric power and complex ducting, while alternative passive heat recovery systems in the form of roof or chimney-based solutions are limited to low rise buildings. This paper describes a biomimetic concept for natural ventilation with heat recovery (NVHR). The NVHR system mimics the process of water/mineral extraction from urine in the Loop of Henle (part of human kidney). Simulations on a facade-integrated Chamber successfully imitated the geometry and behaviour of the Loop of Henle (LoH). Using a space measuring 12 m2 in area and assuming two heat densities of 18.75 W/m2 (single occupancy) or 30 W/m2 (double occupancy), the maximum indoor temperatures achievable are up to 19.3 °C and 22.3 °C respectively. These come with mean relative ventilation rates of 0.92 air changes per hour (ACH) or 10.7 L·s−1 and 0.92 ACH (11.55 L·s−1), respectively, for the month of January. With active heating and single occupant, the LoH Chamber consumes between 65.7% and 72.1% of the annual heating energy required by a similar naturally ventilated space without heat recovery. The LoH Chamber could operate as stand-alone indoor cabinet, benefitting refurbishment of buildings and evading constraints of complicated ducting, external aesthetic or building age.

The paired kidneys play a significant role in the human body due to the multitude of physiological tasks. Complex biochemical processes keep the sensitive electrolyte and water balance stable and thus ensure the organism's ability to adapt to exogenous and endogenous factors, which is essential for survival. The drug class of diuretics includes substances with very differing pharmacological characteristics. The functioning of the nephron is therefore indispensable for a deeper understanding of the pharmacodynamics, pharmacokinetics and side effect profile of diuretics. In the treatment of acute heart failure with pulmonary congestion, certain diuretics represent an important therapeutic option to counteract hypervolemia and thus an increase in preload. According to current data, diuretics have no proven benefits in the treatment or prevention of acute kidney injury but they can counteract hypervolemia and under certain conditions even reduce the use of renal replacement procedures., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Diuretic treatment is the mainstay for management of congestive heart failure in horses, and its use has been restricted to injectable medications because no currently data supports the use of PO administered loop diuretics. Objectives: To determine the pharmacokinetic and pharmacodynamic properties of PO administered torsemide and, determine if PO administered torsemide, could be used as an alternative to injectable diuretics in the horse. Animals: Six healthy adult mares. Methods: A 2‐phase, prospective study, that consisted of pharmacokinetic profiling of a single dose (6 mg/kg PO) and pharmacodynamic effects of long‐term torsemide administration (2 mg/kg PO q12h) for 6 days in healthy horses. Results: Pharmacokinetic analysis identified a peak concentration (Cmax) of 10.14 µg/mL (range, 6.79–14.69 µg/mL) and elimination half‐life (T1/2) 9.2 hours (range, 8.4–10.4 hours). The area under the plasma drug concentration over time curve (AUC) was 80.7 µg × h/mL (range, 56.5–117.2 µg × h/mL). A statistically significant increase in urine volume and decrease in urine specific gravity were found from day 0 (baseline) to day 6 (P < .0001). Significant alterations in biochemical variables included hyponatremia, hypokalemia, hypochloremia, and increased serum creatinine concentration. Mean arterial blood pressure significantly decreased on day 6 (57.7 ± 8.8 mm Hg, P = .001) as compared with baseline (78 ± 6.1 mm Hg). Serum aldosterone concentrations significantly increased after 6 days of torsemide administration (P = .0006). Conclusions and Clinical Importance: PO administered torsemide (4 mg/kg/day) successfully reached therapeutic concentrations in blood, induced clinically relevant diuresis, and resulted in moderate pre‐renal azotemia and electrolyte disturbances. [ABSTRACT FROM AUTHOR]

Osteoblast activating peptide (OBAP) is a newly discovered peptide detected in the rat stomach, which has a major role in osteogenesis. Recently, we revealed its localization in the parietal cells of the rat stomach. There have been no data regarding OBAP expression in the kidney, despite its role in calcium reabsorption in renal tubules. The current study aimed to inspect the expression of OBAP in the kidney of twelve 10-week-old male C3H/HeNJc1 mice using immunohistochemistry, and immunoelectron microscopic localization. The immunohistochemical investigation revealed an OBAP positive reaction mainly in the medulla, which was stronger than the cortex of the kidney and was concentrated in the distal convoluted tubules (DCT), connecting tubules (CT), and the thick limbs of the loop of Henle (HL). Moreover, we clarified that the OBAP was co-distributed with ghrelin and calbindin (markers of the DCT). Interestingly, immunoelectron microscopy demonstrated that OBAP was concentrated in the mitochondrial inner membrane of the DCT and CT. Based on these results, it was concluded that the mitochondria of the DCT, CT, and HL of the mice kidney generate OBAP. Furthermore, our results suggest that OBAP might have a role in the regulation of calcium reabsorption by the renal tubule; however, further investigations are required to clarify this potential role. [ABSTRACT FROM AUTHOR]

The nephron is the functional unit of the kidney involved in the critical interplay of fluid and electrolyte homeostasis by glomerular filtration, selective tubular reabsorption and secretion. This article will discuss the structure and function of each segment of the nephron, and the physiology pertaining to the formation of urine. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a syndrome of reduced glomerular filtration rate and urine production caused by a number of different diseases. It is associated with renal tissue damage. This tissue damage can cause tubular atrophy and interstitial fibrosis that leads to nephron loss and progression of chronic kidney disease (CKD). This review describes the incommon mechanisms behind tissue damage in AKI caused by different underlying diseases. Comparing six high-quality microarray studies of renal gene expression after AKI in disease models (gram-negative sepsis, gram-positive sepsis, ischemiareperfusion, malignant hypertension, rhabdomyolysis, and cisplatin toxicity) identified 5,254 differentially expressed genes in at least one of the AKI models; 66% of genes were found only in one model, showing that there are unique features to AKI depending on the underlying disease. There were in-common features in the form of four genes that were differentially expressed in all six models, 49 in at least five, and 215 were found in common between at least four models. Gene ontology enrichment analysis could be broadly categorized into the injurious processes hypoxia, oxidative stress, and inflammation, as well as the cellular outcomes of cell death and tissue remodeling in the form of epithelial-to-mesenchymal transition. Pathway analysis showed that MYC is a central connection in the network of activated genes in-common to AKI, which suggests that it may be a central regulator of renal gene expression in tissue injury during AKI. The outlining of this molecular network may be useful for understanding progression from AKI to CKD. [ABSTRACT FROM AUTHOR]

The thick ascending limb (TAL) of Henle's loop is a crucial segment for many tasks of the nephron. Indeed, the TAL is not only a mainstay for reabsorption of sodium (Na+), potassium (K+), and divalent cations such as calcium (Ca2+) and magnesium (Mg2+) from the luminal fluid, but also has an important role in urine concentration, overall acid-base homeostasis, and ammonia cycle. Transcellular Na+ transport along the TAL is a prerequisite for Na+, K+, Ca2+, Mg2+ homeostasis, and water reabsorption, the latter through its contribution in the generation of the cortico-medullar osmotic gradient. The role of this nephron site in acid-base balance, via bicarbonate reabsorption and acid secretion, is sometimes misunderstood by clinicians. This review describes in detail these functions, reporting in addition to the well-known molecular mechanisms, some novel findings from the current literature; moreover, the pathophysiology and the clinical relevance of primary or acquired conditions caused by TAL dysfunction are discussed. Knowing the physiology of the TAL is fundamental for clinicians, for a better understanding and management of rare and common conditions, such as tubulopathies, hypertension, and loop diuretics abuse. [ABSTRACT FROM AUTHOR]

Carbonic anhydrase II (CAII) is expressed along the nephron where it interacts with a number of transport proteins augmenting their activity. Aquaporin-1 (AQP1) interacts with CAII to increase water flux through the water channel. Both CAII and aquaporin-1 are expressed in the thin descending limb (TDL); however, the physiological role of a CAII-AQP1 interaction in this nephron segment is not known. To determine if CAII was required for urinary concentration, we studied water handling in CAII-deficient mice. CAII-deficient mice demonstrate polyuria and polydipsia as well as an alkaline urine and bicarbonaturia, consistent with a type III renal tubular acidosis. Natriuresis and hypercalciuria cause polyuria, however, CAII-deficient mice did not have increased urinary sodium nor calcium excretion. Further examination revealed dilute urine in the CAII-deficient mice. Urinary concentration remained reduced in CAII-deficient mice relative to wild-type animals even after water deprivation. The renal expression and localization by light microscopy of NKCC2 and aquaporin-2 was not altered. However, CAII-deficient mice had increased renal AQP1 expression. CAII associates with and increases water flux through aquaporin-1. Water flux through aquaporin-1 in the TDL of the loop of Henle is essential to the concentration of urine, as this is required to generate a concentrated medullary interstitium. We therefore measured cortical and medullary interstitial concentration in wild-type and CAII-deficient mice. Mice lacking CAII had equivalent cortical interstitial osmolarity to wild-type mice: however, they had reduced medullary interstitial osmolarity. We propose therefore that reduced water flux through aquaporin-1 in the TDL in the absence of CAII prevents the generation of a maximally concentrated medullary interstitium. This, in turn, limits urinary concentration in CAII deficient mice. [ABSTRACT FROM AUTHOR]

The loop diuretic furosemide has an action to inhibit Na+-K+-2Cl− co-transporter at the thick ascending limb of Henle's loop resulting in diuresis. Furosemide also has the non-diuretic effects by binding to GABA-A receptor which may involve the gastrointestinal tract. The aim of this study was to investigate the effects of furosemide on smooth muscle contractions in mice ileum and proximal colon. Each intestinal segment suspended in an organ bath was connected to a force transducer. Signal output of mechanical activity was amplified and recorded for analysis using PowerLab System. After equilibration, the intestine was directly exposed to furosemide, GABA, GABA-A receptor agonist (muscimol), or muscarinic receptor antagonist (atropine). Furosemide (50, 100 and 500 μmol L−1) acutely reduced the amplitude of ileal and colonic contraction. In the ileum, 1 mmol L−1 GABA and 10-60 μmol L−1 muscimol significantly increased the amplitude, whereas in the colon, 50-100 mmol L−1 GABA and 60 μmol L−1 muscimol decreased the contractions. The contractions were also significantly suppressed by atropine. To investigate the mechanisms underlying the inhibiting effect of furosemide, furosemide was added to the organ bath prior to the addition of muscimol or atropine. A comparison of furosemide combined with muscimol or atropine group and furosemide group showed no significant difference of the ileal contraction, but the amplitude of colonic contraction significantly decreased when compared to adding furosemide alone. These results suggest that furosemide can reduce the ileal and proximal colonic contraction mediated by blocking and supporting of GABA-A receptor, respectively, resulting in decreased acetylcholine release. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is a condition characterized by progressive and irreversible deterioration of renal function due to the reduction of nephron mass for a period of at least three months. The prevalence of CKD is roughly 10% in the general population but increases with age, affecting more than one-third of people older than 65. Frailty is a condition usually found in elderly people, characterized by weakness, motility, and balance issues, with a declined ability to resist stressors leading to increased risks of adverse health outcomes including falls, fracture, hospitalization, institutionalization, disability, dependence, dementia, poor quality of life, and death. There is interdependence between CKD and normal ageing whereby CKD makes ageing more accelerated and pronounced (senescence), whereas senescence accelerates chronic nephropathy's progression. Frailty status catalyzes this spiral, with renal and systemic consequences, phenomenon which can be named senescent nephropathy. In conclusion, senescent nephropathy is a new renal syndrome that should be taken into account, and we must try to handle its appearance and progression not only by applying nephron prevention measurements but also by diagnosis and treating frailty in the CKD population. [ABSTRACT FROM AUTHOR]

Background: The likelihood of a Randall's plug composed of calcium oxalate monohydrate (COM) forming by the free particle mechanism in a model of kidney with a structure recently described by Robertson was examined at the most favourable conditions for the considered mechanism.Methods: The Robertson model of the kidney is used in the following development. The classical theory of crystallization was used for calculations.Results: Initial COM nuclei were assumed to form at the beginning of the ascending loop of Henle where the supersaturation with respect to COM has been shown to reach the threshold level for spontaneous nucleation. Nucleation proceeds by a heterogeneous mechanism. The formed particles are transported in the nephron by a laminar flow of liquid with a parabolic velocity profile. Particles travel with a velocity dependent on their position in the cross-section of the nephron assumed to be straight tubule with smooth walls and without any sharp bends and kinks. These particles move faster with time as they grow as a result of being surrounded by the supersaturated liquid. Individual COM particles (crystals) can reach maximum diameter of 5.2 × 10-6 m, i.e. 5.2 μm, at the opening of the CD and would thus always be washed out of the CD into the calyx regardless of the orientation of the CD. Agglomeration of COM crystals forms a fractal object with an apparent density lower than the density of solid COM. The agglomerate that can block the beginning of the CD is composed of more crystals than are available even during crystaluria. Moreover the settling velocity of agglomerate blocking the opening of the CD is lower than the liquid flow and thus such agglomerate would be washed out even from upward-draining CD.Conclusions: The free particle mechanism may be responsible for the formation of a Randall's plug composed by COM only in specific infrequent cases such as an abnormal structure of kidney. Majority of incidences of Randall's plug development by COM are caused by mechanism different from the free particle mechanism. [ABSTRACT FROM AUTHOR]

The formation of the proper number of nephrons requires a tightly regulated balance between renal progenitor cell self-renewal and differentiation. The molecular pathways that regulate the transition from renal progenitor to renal vesicle are not well understood. Here, we show that Sall1interacts with the nucleosome remodeling and deacetylase complex (NuRD) to inhibit premature differentiation of nephron progenitor cells. Disruption of Sall1-NuRD in vivo in knock-in mice (ΔSRM) resulted in accelerated differentiation of nephron progenitors and bilateral renal hypoplasia. Transcriptional profiling of mutant kidneys revealed a striking pattern in which genes of the glomerular and proximal tubule lineages were either unchanged or upregulated, and those in the loop of Henle and distal tubule lineages were downregulated. These global changes in gene expression were accompanied by a significant decrease in THP-, NKCC2- and AQP1- positive loop of Henle nephron segments in mutant ΔSRM kidneys. These findings highlight an important function of Sall1-NuRD interaction in the regulation of Six2-positive multipotent renal progenitor cells and formation of the loop of Henle. [ABSTRACT FROM AUTHOR]

MCT14 is an orphan transporter belonging to the SLC16 transporter family mediating the transport of monocarboxylates, aromatic amino acids, creatine, and thyroid hormones. The expression, tissue localization, regulation, and function of MCT14 are unknown. In mouse MCT14 mRNA abundance is highest in kidney. Using a newly developed and validated antibody, MCT14 was localized to the luminal membrane of the thick ascending limb of the loop of Henle colocalizing in the same cells with uromodulin and NKCC2. MCT14 mRNA and protein was found to be highly regulated by dietary phosphate intake in mice being increased by high dietary phosphate intake at both mRNA and protein level. In order to identify the transport substrate(s), we expressed MCT14 in Xenopus laevis oocytes where MCT14 was integrated into the plasma membrane. However, no transport was discovered for the classic substrates of the SLC16 family nor for phosphate. In summary, MCT14 is an orphan transporter regulated by phosphate and highly enriched in kidney localizing to the luminal membrane of one specific nephron segment. [ABSTRACT FROM AUTHOR]

Claudins are a family of proteins that forms paracellular barriers and pores determining tight junctions (TJ) permeability. Claudin-16 and -19 are pore forming TJ proteins allowing calcium and magnesium reabsorption in the thick ascending limb of Henle's loop (TAL). Loss-of-function mutations in the encoding genes, initially identified to cause Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis (FHHNC), were recently shown to be also involved in Amelogenesis Imperfecta (AI). In addition, both claudins were expressed in the murine tooth germ and Claudin-16 knockout (KO) mice displayed abnormal enamel formation. Claudin-3, an ubiquitous claudin expressed in epithelia including kidney, acts as a barrier-forming tight junction protein. We determined that, similarly to claudin-16 and claudin-19, claudin-3 was expressed in the tooth germ, more precisely in the TJ located at the apical end of secretory ameloblasts. The observation of Claudin-3 KO teeth revealed enamel defects associated to impaired TJ structure at the secretory ends of ameloblasts and accumulation ofmatrix proteins in the forming enamel. Thus, claudin-3 protein loss-of-function disturbs amelogenesis similarly to claudin-16 loss-of-function, highlighting the importance of claudin proteins for the TJ structure. These findings unravel that loss-of-function of either pore or barrier-forming TJ proteins leads to enamel defects. Hence, the major structural function of claudin proteins appears essential for amelogenesis. [ABSTRACT FROM AUTHOR]