Correlation between urine anion gap and urine ammonia-creatinine ratio in healthy cats and cats with kidney disease.

BACKGROUND: Ammonium excretion decreases as kidney function decreases in several species, including cats, and may have predictive or prognostic value in patients with chronic kidney disease (CKD). Urine ammonia measurement is not readily available in clinical practice, and urine anion gap (UAG) has been proposed as a surrogate test. OBJECTIVES: Evaluate the correlation between urine ammonia-to-creatinine ratio (UACR) and UAG in healthy cats and those with CKD and determine if a significant difference exists between UAG of healthy cats and cats with CKD. ANIMALS: Urine samples collected from healthy client-owned cats (n = 59) and those with stable CKD (n = 17). METHODS: Urine electrolyte concentrations were measured using a commercial chemistry analyzer and UAG was calculated as ([sodium] + [potassium]) - [chloride]. Urine ammonia and creatinine concentrations had been measured previously using commercially available enzymatic assays and used to calculate UACR. Spearman's rank correlation coefficient between UAG and UACR was calculated for both groups. The UAG values of healthy cats and cats with CKD were assessed using the Mann-Whitney test (P < .05). RESULTS: The UAG was inversely correlated with UACR in healthy cats (P < .002, r0 = -0.40) but not in cats with CKD (P = .55; r0 = -0.15). A significant difference was found between UAG in healthy cats and those with CKD (P < .001). CONCLUSIONS AND CLINICAL IMPORTANCE: The UAG calculation cannot be used as a substitute for UACR in cats. The clinical relevance of UAG differences between healthy cats and those with CKD remains unknown.

Development of a reference interval for urinary ammonia-to-creatinine ratio in feline patients.

BACKGROUND: Disruption of acid-base homeostasis can lead to many clinical problems. Ammonia excretion by the kidneys is critical to maintaining acid-base homeostasis through bicarbonate production. Measurement of ammonia excretion may help determine if the kidneys are properly functioning in maintaining acid-base balance. Reference intervals are essential tools for clinical decision-making but do not currently exist for urinary ammonia-to-creatinine ratio (UACR) in feline patients. OBJECTIVE: This study aimed to generate a reference interval (RI) for UACR in healthy adult cats. METHODS: The study used samples from client-owned adult healthy cats that presented to the University of Florida Primary Care and Dentistry service (n = 92). Physical examination, serum biochemistry, urinalysis, urine ammonia, and creatinine concentrations were measured. Cats were excluded if there were significant abnormalities in their urinalysis or biochemistry panel. The RI for UACR was calculated according to the recommendation of the American Society for Veterinary Clinical Pathology. The UACR was evaluated for correlation with serum bicarbonate, weight, age, and sex. RESULTS: The RI for UACR was 3.4-20.7 with 90% confidence intervals for the lower and upper limits of (3.0-3.7) and (16.0-23.7), respectively. No significant correlation with age, sex, or weight was found. There was no discernable relationship between serum bicarbonate and UACR. CONCLUSIONS: Establishing an RI for UACR in healthy adult cats will allow further studies to determine if changes in UACR are observed during specific disease states.

A phenotypically robust model of spinal and bulbar muscular atrophy in Drosophila.

Spinal and bulbar muscular atrophy (SBMA) is an X-linked disorder that affects males who inherit the androgen receptor (AR) gene with an abnormal CAG triplet repeat expansion. The resulting protein contains an elongated polyglutamine (polyQ) tract and causes motor neuron degeneration in an androgen-dependent manner. The precise molecular sequelae of SBMA are unclear. To assist with its investigation and the identification of therapeutic options, we report here a new model of SBMA in Drosophila melanogaster. We generated transgenic flies that express the full-length, human AR with a wild-type or pathogenic polyQ repeat. Each transgene is inserted into the same safe harbor site on the third chromosome of the fly as a single copy and in the same orientation. Expression of pathogenic AR, but not of its wild-type variant, in neurons or muscles leads to consistent, progressive defects in longevity and motility that are concomitant with polyQ-expanded AR protein aggregation and reduced complexity in neuromuscular junctions. Additional assays show adult fly eye abnormalities associated with the pathogenic AR species. The detrimental effects of pathogenic AR are accentuated by feeding flies the androgen, dihydrotestosterone. This new, robust SBMA model can be a valuable tool toward future investigations of this incurable disease.

Sex differences in renal transporters: assessment and functional consequences.

Mammalian kidneys are specialized to maintain fluid and electrolyte homeostasis. The epithelial transport processes along the renal tubule that match output to input have long been the subject of experimental and theoretical study. However, emerging data have identified a new dimension of investigation: sex. Like most tissues, the structure and function of the kidney is regulated by sex hormones and chromosomes. Available data demonstrate sex differences in the abundance of kidney solute and electrolyte transporters, establishing that renal tubular organization and operation are distinctly different in females and males. Newer studies have provided insights into the physiological consequences of these sex differences. Computational simulations predict that sex differences in transporter abundance are likely driven to optimize reproduction, enabling adaptive responses to the nutritional requirements of serial pregnancies and lactation - normal life-cycle changes that challenge the ability of renal transporters to maintain fluid and electrolyte homeostasis. Later in life, females may also undergo menopause, which is associated with changes in disease risk. Although numerous knowledge gaps remain, ongoing studies will provide further insights into the sex-specific mechanisms of sodium, potassium, acid-base and volume physiology throughout the life cycle, which may lead to therapeutic opportunities.

Lysine 117 on ataxin-3 modulates toxicity in Drosophila models of Spinocerebellar Ataxia Type 3.

Ataxin-3 (Atxn3) is a deubiquitinase with a polyglutamine (polyQ) repeat tract whose abnormal expansion causes the neurodegenerative disease, Spinocerebellar Ataxia Type 3 (SCA3; also known as Machado-Joseph Disease). The ubiquitin chain cleavage properties of Atxn3 are enhanced when the enzyme is itself ubiquitinated at lysine (K) at position 117: in vitro, K117-ubiqutinated Atxn3 cleaves poly-ubiquitin markedly more rapidly compared to its unmodified counterpart. How polyQ expansion causes SCA3 remains unclear. To gather insights into the biology of disease of SCA3, here we posited the question: is K117 important for toxicity caused by pathogenic Atxn3? To answer this question, we generated transgenic Drosophila lines that express full-length, human, pathogenic Atxn3 with 80 polyQ with an intact or mutated K117. We found that mutating K117 mildly enhances the toxicity and aggregation of pathogenic Atxn3. An additional transgenic line that expresses Atxn3 without any K residues confirms increased aggregation of pathogenic Atxn3 whose ubiquitination is perturbed. These findings suggest that Atxn3 ubiquitination is a regulatory step of SCA3, in part by modulating its aggregation.

Use of serum osmolality to identify heart disease stage in dogs and relationship to mathematical chloride correction.

BACKGROUND: Heart failure-associated hypochloremia can be depletional from diuretics or dilutional from water retention. Serum osmolality reflects water balance but has not been evaluated in dogs with heart disease. HYPOTHESIS: To determine if serum osmolality is related to heart disease stage and amount of mathematical correction of serum chloride (Cl- ) concentrations in healthy dogs and dogs with myxomatous mitral valve degeneration (MMVD). ANIMALS: Seventy-seven dogs (20 healthy, 25 Stage B MMVD, 32 Stage C/D MMVD). METHODS: Serum Cl- concentrations were mathematically corrected. Osmolality was calculated (calOsm) and directly measured by freezing point depression (dmOsm) and compared by Bland-Altman analysis. Biochemical variables and osmolality were compared among healthy, Stage B, and Stage C/D dogs. Correlations were explored between osmolality and biochemical variables. Median and range are presented. P < .05 was considered significant. RESULTS: The calOsm was different among groups (P = .003), with Stage B (310 mOsm/kg; 306, 316) and C/D dogs (312 mOsm/kg; 308, 319) having higher calOsm than healthy dogs (305 mOsm/kg; 302, 308). Osmolality methods were moderately correlated (P < .0001, rs = .46) but with proportional bias and poor agreement. The amount of Cl- correction was negatively correlated with calOsm (P < .0001, rs = -.78) and dmOsm (P = .004, rs = -.33). Serum bicarbonate concentration was negatively correlated with Cl- (P < .0001, rs = -.67). CONCLUSIONS AND CLINICAL IMPORTANCE: Dogs with Stage B and Stage C/D heart disease had higher calOsm than healthy dogs. Osmolality was inversely related to the amount of Cl- correction, which supports its use in assessing relative body water content. Poor agreement between calOsm and dmOsm prevents methodological interchange.

Lysine 117 on ataxin-3 modulates toxicity in Drosophila models of Spinocerebellar Ataxia Type 3.

Ataxin-3 (Atxn3) is a deubiquitinase with a polyglutamine (polyQ) repeat tract whose abnormal expansion causes the neurodegenerative disease, Spinocerebellar Ataxia Type 3 (SCA3; also known as Machado-Joseph Disease). The ubiquitin chain cleavage properties of Atxn3 are enhanced when it is ubiquitinated at lysine (K) at position 117. K117-ubiqutinated Atxn3 cleaves poly-ubiquitin more rapidly in vitro compared to its unmodified counterpart and this residue is also important for Atxn3 roles in cell culture and in Drosophila melanogaster . How polyQ expansion causes SCA3 remains unclear. To gather insight into the biology of disease of SCA3, here we posited the question: is K117 important for toxicity caused by Atxn3? We generated transgenic Drosophila lines that express full-length, human, pathogenic Atxn3 with 80 polyQ with an intact or mutated K117. We found that K117 mutation mildly enhances the toxicity and aggregation of pathogenic Atxn3 in Drosophila . An additional transgenic line that expresses Atxn3 without any K residues confirms increased aggregation of pathogenic Atxn3 whose ubiquitination is perturbed. These findings suggest Atxn3 ubiquitination as a regulatory step of SCA3, in part by modulating its aggregation.

Urinary Ammonium in Clinical Medicine: Direct Measurement and the Urine Anion Gap as a Surrogate Marker During Metabolic Acidosis.

Ammonium is the most important component of urinary acid excretion, normally accounting for about two-third of net acid excretion. In this article, we discuss urine ammonium not only in the evaluation of metabolic acidosis but also in other clinical conditions such as chronic kidney disease. Different methods to measure urine NH4+ that have been employed over the years are discussed. The enzymatic method used by clinical laboratories in the United States to measure plasma ammonia via the glutamate dehydrogenase can be used for urine ammonium. The urine anion gap calculation can be used as a rough marker of urine ammonium in the initial bedside evaluation of metabolic acidosis such as in distal renal tubular acidosis. Urine ammonium measurements, however, should be made more available in clinical medicine for a precise evaluation of this important component of urinary acid excretion.

An Update on Kidney Ammonium Transport Along the Nephron.

Acid-base homeostasis is critical to the maintenance of normal health. The kidneys have a central role in bicarbonate generation, which occurs through the process of net acid excretion. Renal ammonia excretion is the predominant component of renal net acid excretion under basal conditions and in response to acid-base disturbances. Ammonia produced in the kidney is selectively transported into the urine or the renal vein. The amount of ammonia produced by the kidney that is excreted in the urine varies dramatically in response to physiological stimuli. Recent studies have advanced our understanding of ammonia metabolism's molecular mechanisms and regulation. Ammonia transport has been advanced by recognizing that the specific transport of NH3 and NH4+ by specific membrane proteins is critical to ammonia transport. Other studies show that proximal tubule protein, NBCe1, specifically the A variant, significantly regulates renal ammonia metabolism. This review discusses these critical aspects of the emerging features of ammonia metabolism and transport.

Stump pyometra in a spayed female dog secondary to tamoxifen.

OBJECTIVE: To describe a complication associated with the long-term use of tamoxifen for the treatment of sclerosing encapsulating peritonitis in a dog. CASE SUMMARY: A 2-year-old female spayed poodle cross was evaluated for a stump pyometra. The dog was diagnosed with sclerosing encapsulating peritonitis a year prior and was treated with tamoxifen, an oestrogen receptor antagonist, for treatment of the disease. The dog developed a swollen vulva with vulvar discharge and a stump pyometra was diagnosed on ultrasound. Hormonal testing was submitted to evaluate for an ovarian remnant and the dog underwent an exploratory laparotomy, where the uterine stump was removed. No ovarian remnant tissue was identified intra-operatively, and hormonal testing (anti-Müllerian hormone, progesterone, oestradiol) and histopathology were consistent with the absence of ovarian tissue. The tamoxifen was discontinued. The dog recovered uneventfully after surgery. NEW OR UNIQUE INFORMATION PROVIDED: This report describes a complication of treatment of a rarely described clinical disease. While most cases of stump pyometra involve ovarian remnant syndrome, this case report describes a stump pyometra in a dog without remnant tissue that was undergoing treatment with tamoxifen. Tamoxifen has been reported to cause pyometra in intact female dogs. To the authors' knowledge, this is the first case report to describe a stump pyometra in a spayed female dog, secondary to the use of tamoxifen.

The proximal tubule through an NBCe1-dependent mechanism regulates collecting duct phenotypic and remodeling responses to acidosis.

The renal response to acid-base disturbances involves phenotypic and remodeling changes in the collecting duct. This study examines whether the proximal tubule controls these responses. We examined mice with genetic deletion of proteins present only in the proximal tubule, either the A variant or both A and B variants of isoform 1 of the electrogenic Na+-bicarbonate cotransporter (NBCe1). Both knockout (KO) mice have spontaneous metabolic acidosis. We then determined the collecting duct phenotypic responses to this acidosis and the remodeling responses to exogenous acid loading. Despite the spontaneous acidosis in NBCe1-A KO mice, type A intercalated cells in the inner stripe of the outer medullary collecting duct (OMCDis) exhibited decreased height and reduced expression of H+-ATPase, anion exchanger 1, Rhesus B glycoprotein, and Rhesus C glycoprotein. Combined kidney-specific NBCe1-A/B deletion induced similar changes. Ultrastructural imaging showed decreased apical plasma membrane and increased vesicular H+-ATPase in OMCDis type A intercalated cell in NBCe1-A KO mice. Next, we examined the collecting duct remodeling response to acidosis. In wild-type mice, acid loading increased the proportion of type A intercalated cells in the connecting tubule (CNT) and OMCDis, and it decreased the proportion of non-A, non-B intercalated cells in the connecting tubule, and type B intercalated cells in the cortical collecting duct (CCD). These changes were absent in NBCe1-A KO mice. We conclude that the collecting duct phenotypic and remodeling responses depend on proximal tubule-dependent signaling mechanisms blocked by constitutive deletion of proximal tubule NBCe1 proteins.NEW & NOTEWORTHY This study shows that the proximal tubule regulates collecting duct phenotypic and remodeling responses to acidosis.

A survey of protein interactions and posttranslational modifications that influence the polyglutamine diseases.

The presence and aggregation of misfolded proteins has deleterious effects in the nervous system. Among the various diseases caused by misfolded proteins is the family of the polyglutamine (polyQ) disorders. This family comprises nine members, all stemming from the same mutation-the abnormal elongation of a polyQ repeat in nine different proteins-which causes protein misfolding and aggregation, cellular dysfunction and disease. While it is the same type of mutation that causes them, each disease is distinct: it is influenced by regions and domains that surround the polyQ repeat; by proteins with which they interact; and by posttranslational modifications they receive. Here, we overview the role of non-polyQ regions that control the pathogenicity of the expanded polyQ repeat. We begin by introducing each polyQ disease, the genes affected, and the symptoms experienced by patients. Subsequently, we provide a survey of protein-protein interactions and posttranslational modifications that regulate polyQ toxicity. We conclude by discussing shared processes and pathways that bring some of the polyQ diseases together and may serve as common therapeutic entry points for this family of incurable disorders.

Case Report: Septic Pericarditis With Achromobacter xyloxidans in an Immunosuppressed Dog.

A 5-year-old female spayed French Bulldog presented for anorexia and increased respiratory rate. On presentation, she was dyspneic with stridor and increased bronchovesicular sounds. Point-of-care ultrasound identified pericardial effusion. Thoracic radiographs identified pleural effusion, a wide cranial mediastinum, and multifocal unstructured interstitial pulmonary opacities. Bloodwork revealed a moderate leukocytosis characterized by a mature neutrophilia with a left shift, hypoalbuminemia, mildly increased alkaline phosphatase activity, and moderate hypokalemia. Thoracic CT findings revealed moderate pericardial and bilateral pleural effusion, mediastinal effusion, and moderate cranial mediastinal lymphadenopathy. Diagnostic thoracocentesis and pericardiocentesis revealed septic exudates with bacilli. Two days later, a median sternotomy and pericardiectomy were performed. Aerobic cultures of the effusions grew Achromobacter xylosoxidans ss deitrificans. The patient was treated with Amoxicillin-clavulanate and enrofloxacin for 12 weeks and clinically fully recovered. Achromobacter xylosoxidans has not been reported as a cause of purulent pericarditis and pyothorax in a dog. Uniquely, this patient is suspected of developing this infection secondary to immunosuppression.

Acid-base effects of combined renal deletion of NBCe1-A and NBCe1-B.

The molecular mechanisms regulating ammonia metabolism are fundamental to acid-base homeostasis. Deletion of the A splice variant of Na+-bicarbonate cotransporter, electrogenic, isoform 1 (NBCe1-A) partially blocks the effect of acidosis to increase urinary ammonia excretion, and this appears to involve the dysregulated expression of ammoniagenic enzymes in the proximal tubule (PT) in the cortex but not in the outer medulla (OM). A second NBCe1 splice variant, NBCe1-B, is present throughout the PT, including the OM, where NBCe1-A is not present. The purpose of the present study was to determine the effect of combined renal deletion of NBCe1-A and NBCe1-B on systemic and PT ammonia metabolism. We generated NBCe1-A/B deletion using Cre-loxP techniques and used Cre-negative mice as controls. As renal NBCe1-A and NBCe1-B expression is limited to the PT, Cre-positive mice had PT NBCe1-A/B deletion [PT-NBCe1-A/B knockout (KO)]. Although on a basal diet, PT-NBCe1-A/B KO mice had severe metabolic acidosis, yet urinary ammonia excretion was not changed significantly. PT-NBCe1-A/B KO decreased the expression of phosphate-dependent glutaminase and phosphoenolpyruvate carboxykinase and increased the expression of glutamine synthetase, an ammonia-recycling enzyme, in PTs in both the cortex and OM. Exogenous acid loading increased ammonia excretion in control mice, but PT-NBCe1-A/B KO prevented any increase. PT-NBCe1-A/B KO significantly blunted acid loading-induced changes in phosphate-dependent glutaminase, phosphoenolpyruvate carboxykinase, and glutamine synthetase expression in PTs in both the cortex and OM. We conclude that NBCe1-B, at least in the presence of NBCe1-A deletion, contributes to PT ammonia metabolism in the OM and thereby to systemic acid-base regulation.NEW & NOTEWORTHY The results of the present study show that combined deletion of both A and B splice variants of electrogenic Na+-bicarbonate cotransporter 1 from the proximal tubule impairs acid-base homeostasis and completely blocks changes in ammonia excretion in response to acidosis, indicating that both proteins are critical to acid-base homeostasis.

Ubiquitin-binding site 1 of pathogenic ataxin-3 regulates its toxicity in Drosophila models of Spinocerebellar Ataxia Type 3.

Spinocerebellar Ataxia Type 3 (SCA3) is a member of the family of polyglutamine (polyQ) diseases that are caused by anomalous CAG triplet repeat expansions in several genes. SCA3 results from abnormal polyQ expansion in the deubiquitinase (DUB), ataxin-3 (Atxn3). To understand the role of the different domains of mutant Atxn3 on its pathogenicity, with the hope that they can be explored for therapeutic interventions, we have systematically studied their individual and collective effects on its toxicity. One such domain is ubiquitin-binding site 1 (UbS1) on the catalytic domain of Atxn3; UbS1 is necessary for the enzymatic activity of Atxn3. Here, we investigated the importance of UbS1 on the toxicity of pathogenic Atxn3. We generated transgenic Drosophila melanogaster lines that express polyQ-expanded Atxn3 with and without a functional UbS1. We found that mutating UbS1 markedly exacerbates the toxicity of pathogenic Atxn3. Additional studies indicated that UbS1 regulates the toxicity of Atxn3 not by affecting its aggregation or sub-cellular localization, but by impacting its role in ubiquitin processing. Our findings provide additional insights into the role of Atxn3's domains in the pathogenicity of SCA3.

Establishment of an RI for the urine ammonia-to-creatinine ratio in dogs.

BACKGROUND: Ammonia is produced and excreted by the kidney, contributing to systemic acid-base homeostasis through the production of bicarbonate. Disorders of acid-base balance can lead to many clinical problems and measuring ammonia excretion helps in determining if the kidneys are responding to acid-base challenges appropriately. Reference intervals are integral to clinical decision-making, and there is no current RI for the urine ammonia-to-creatinine ratio (UACR) in dogs. OBJECTIVE: This study aimed to generate an RI for the UACR in healthy adult dogs. METHODS: The study used adult, client-owned dogs that were presented to the University of Florida Primary Care and Dentistry service (n = 60). Physical examinations were performed and serum chemistry and urinalysis samples were obtained. Urine ammonia and creatinine concentrations were determined. Dogs were excluded if there were significant abnormalities in either their urinalysis or serum chemistry results. The RI for the UACR was calculated according to the recommendation of the American Society for Veterinary Clinical Pathology. Data were evaluated for correlation with serum bicarbonate, weight, age, and sex. RESULTS: The RIs for the UACR were 0.16-23.69 with 90% confidence intervals for the lower and upper limits of (0.13-1.17) and (20.50-23.75), respectively. No significant impact of age, sex, or weight was found. There was no discernable relationship between serum bicarbonate and UACR. CONCLUSIONS: Establishing an RI for UACR in healthy adult dogs will allow for further studies to determine if alterations are observed during specific disease states.

Familial nephropathy in Bracchi Italiani: 8 cases (2012-2019).

OBJECTIVE: To characterize the signalment, clinical signs, clinical pathological and histologic findings, and outcome in 8 related Bracchi Italiani with proteinuric kidney disease. ANIMALS: 8 client-owned Bracchi Italiani. PROCEDURES: Health records submitted to the Bracco Italiano Health Foundation and the Bracco Italiano Club of America between 2012 and 2019 were reviewed for dogs with evidence of nephropathy for which histologic diagnoses were obtained. Pedigree, signalment, clinical signs, diagnostic test results (including microscopic examination of kidney tissue samples collected ante- or postmortem), and outcome were acquired. Results were presented as descriptive statistics. RESULTS: The most common clinical sign in affected dogs was inappetence. All dogs were proteinuric, and 4 dogs were azotemic. Seven dogs developed clinical signs of kidney disease and were euthanized a median of 75 days postdiagnosis. Six dogs had glomerular amyloidosis, and 1 dog each had nephrosclerosis and nonamyloidotic fibrillar glomerulopathy. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that the clinical presentation may vary in affected dogs, and proteinuria in young or middle-aged Bracchi Italiani should raise the concern for hereditary nephropathy. Prognosis is likely poor once clinical signs are noted.

Role of the renal androgen receptor in sex differences in ammonia metabolism.

There are sex differences in renal ammonia metabolism and structure, many of which are mediated by testosterone. The goal of the present study was to determine the role of renal expression of testosterone's canonical receptor, androgen receptor (AR), in these sexual dimorphisms. We studied mice with kidney-specific AR deletion [KS-AR-knockout (KO)] generated using Cre/loxP techniques; control mice were Cre-negative littermates (wild type). In male but not female mice, KS-AR-KO increased ammonia excretion, which eliminated sex differences. Although renal structural size typically parallel ammonia excretion, KS-AR-KO decreased kidney size, cortical proximal tubule volume density, and cortical proximal tubule cell height in males-neither were altered in females and collecting duct volume density was unaltered in both sexes. Analysis of key protein involved in ammonia handling showed in male mice that KS-AR-KO increased both phosphoenolpyruvate carboxykinase (PEPCK) and Na+-K+-2Cl- cotransporter (NKCC2) expression and decreased Na+/H+ exchanger isoform 3 (NHE3) and electrogenic Na+-bicarbonate cotransporter 1 (NBCe1)-A expression. In female mice, KS-AR-KO did not alter these parameters. These effects occurred even though KS-AR-KO did not alter plasma testosterone, food intake, or serum Na+, K+, or [Formula: see text] significantly in either sex. In conclusion, AR-dependent signaling pathways in male, but not female, kidneys regulate PEPCK and NKCC2 expression and lead to the sexual differences in ammonia excretion. Opposing effects on NHE3 and NBCe1-A expression likely limit the magnitude of ammonia excretion changes. As AR is not present in the thick ascending limb, the effect of KS-AR-KO on NKCC2 expression is indirect. Finally, AR mediates the greater kidney size and proximal tubule volume density in male compared with female mice.NEW & NOTEWORTHY Sexual dimorphisms in ammonia metabolism involve androgen receptor (AR)-dependent signaling pathways in male, but not female, kidneys that lead to altered proximal tubule (PT), phosphoenolpyruvate carboxykinase, and thick ascending limb Na+-K+-2Cl- cotransporter expression. Adaptive responses in Na+/H+ exchanger 3 and electrogenic Na+-bicarbonate cotransporter 1-A expression limit the magnitude of the effect on ammonia excretion. Finally, the greater kidney size and PT volume density in male mice is the result of PT androgen signaling through AR.

Sex differences in renal ammonia metabolism.

Sexual dimorphic variations are present in many aspects of biology and involve the structure and/or function of nearly every organ system. Acid-base homeostasis is critical for optimal health, and renal ammonia metabolism has a major role in the maintenance of acid-base homeostasis. Recent studies have shown sex-dependent differences in renal ammonia metabolism with regard to both basal ammonia excretion and the response to an exogenous acid load. These sexual dimorphisms are associated with structural changes in the proximal tubule and the collecting duct and variations in the expression of multiple proteins involved in ammonia metabolism and transport. Studies using orchiectomy-induced testosterone deficiency and physiological testosterone replacement have shown that testosterone underlies much of the sex-dependent differences in the proximal tubule. This parallels the finding that the canonical testosterone target receptor, androgen receptor (AR), is present exclusively in the proximal tubule. Thus testosterone, possibly acting through AR activation, regulates multiple components of renal structure and ammonia metabolism. The lack of detectable AR in the remainder of the nephron and collecting duct suggests that some dimorphisms in renal structure and ammonia transporter expression are mediated through mechanisms other than direct testosterone-dependent AR activation. A better understanding of the mechanism and biological implications of sex's effect on renal structure and ammonia metabolism is critical for optimizing our ability to care for both men and women with acid-base disturbances.