Learning Physiology From Inherited Kidney Disorders.

The identification of genes causing inherited kidney diseases yielded crucial insights in the molecular basis of disease and improved our understanding of physiological processes that operate in the kidney. Monogenic kidney disorders are caused by mutations in genes coding for a large variety of proteins including receptors, channels and transporters, enzymes, transcription factors, and structural components, operating in specialized cell types that perform highly regulated homeostatic functions. Common variants in some of these genes are also associated with complex traits, as evidenced by genome-wide association studies in the general population. In this review, we discuss how the molecular genetics of inherited disorders affecting different tubular segments of the nephron improved our understanding of various transport processes and of their involvement in homeostasis, while providing novel therapeutic targets. These include inherited disorders causing a dysfunction of the proximal tubule (renal Fanconi syndrome), with emphasis on epithelial differentiation and receptor-mediated endocytosis, or affecting the reabsorption of glucose, the handling of uric acid, and the reabsorption of sodium, calcium, and magnesium along the kidney tubule.

Empagliflozin in Patients with Chronic Kidney Disease.

BACKGROUND: The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients. METHODS: We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m2 of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m2 with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to <10 ml per minute per 1.73 m2, a sustained decrease in eGFR of ≥40% from baseline, or death from renal causes) or death from cardiovascular causes. RESULTS: A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; P<0.001). Results were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. The rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.86; 95% CI, 0.78 to 0.95; P = 0.003), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular causes (which occurred in 4.0% in the empagliflozin group and 4.6% in the placebo group) or death from any cause (in 4.5% and 5.1%, respectively). The rates of serious adverse events were similar in the two groups. CONCLUSIONS: Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo. (Funded by Boehringer Ingelheim and others; EMPA-KIDNEY ClinicalTrials.gov number, NCT03594110; EudraCT number, 2017-002971-24.).

A RhoA-YAP-c-Myc signaling axis promotes the development of polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder caused by mutations in PKD1 or PKD2 and affects one in 500-1000 humans. Limited treatment is currently available for ADPKD. Here we identify the Hippo signaling effector YAP and its transcriptional target, c-Myc, as promoters of cystic kidney pathogenesis. While transgenic overexpression of YAP promotes proliferation and tubule dilation in mouse kidneys, loss of YAP/TAZ or c-Myc suppresses cystogenesis in a mouse ADPKD model resulting from Pkd1 deficiency. Through a comprehensive kinase inhibitor screen based on a novel three-dimensional (3D) culture of Pkd1 mutant mouse kidney cells, we identified a signaling pathway involving the RhoGEF (guanine nucleotide exchange factor) LARG, the small GTPase RhoA, and the RhoA effector Rho-associated kinase (ROCK) as a critical signaling module between PKD1 and YAP. Further corroborating its physiological importance, inhibition of RhoA signaling suppresses cystogenesis in 3D culture of Pkd1 mutant kidney cells as well as Pkd1 mutant mouse kidneys in vivo. Taken together, our findings implicate the RhoA-YAP-c-Myc signaling axis as a critical mediator and potential drug target in ADPKD.

Mimicking kidney flow shear efficiently induces aggregation of LECT2, a protein involved in renal amyloidosis.

Aggregation of leukocyte cell-derived chemotaxin 2 (LECT2) causes ALECT2, a systemic amyloidosis that affects the kidney and liver. Previous studies established that LECT2 fibrillogenesis is accelerated by the loss of its bound zinc ion and stirring/shaking. These forms of agitation create heterogeneous shear conditions, including air-liquid interfaces that denature proteins, that are not present in the body. Here, we determined the extent to which a more physiological form of mechanical stress-shear generated by fluid flow through a network of narrow channels-drives LECT2 fibrillogenesis. To mimic blood flow through the kidney, where LECT2 and other proteins form amyloid deposits, we developed a microfluidic device consisting of progressively branched channels narrowing from 5 mm to 20 µm in width. Shear was particularly pronounced at the branch points and in the smallest capillaries. Aggregation was induced within 24 h by shear levels that were in the physiological range and well below those required to unfold globular proteins such as LECT2. EM images suggested the resulting fibril ultrastructures were different when generated by laminar flow shear versus shaking/stirring. Importantly, results from the microfluidic device showed the first evidence that the I40V mutation accelerated fibril formation and increased both the size and the density of the aggregates. These findings suggest that kidney-like flow shear, in combination with zinc loss, acts in combination with the I40V mutation to trigger LECT2 amyloidogenesis. These microfluidic devices may be of general use for uncovering mechanisms by which blood flow induces misfolding and amyloidosis of circulating proteins.

Evaluation and Management of Kidney Dysfunction in Advanced Heart Failure: A Scientific Statement From the American Heart Association.

Early identification of kidney dysfunction in patients with advanced heart failure is crucial for timely interventions. In addition to elevations in serum creatinine, kidney dysfunction encompasses inadequate maintenance of sodium and volume homeostasis, retention of uremic solutes, and disrupted endocrine functions. Hemodynamic derangements and maladaptive neurohormonal upregulations contribute to fluctuations in kidney indices and electrolytes that may recover with guideline-directed medical therapy. Quantifying the extent of underlying irreversible intrinsic kidney disease is crucial in predicting whether optimization of congestion and guideline-directed medical therapy can stabilize kidney function. This scientific statement focuses on clinical management of patients experiencing kidney dysfunction through the trajectory of advanced heart failure, with specific focus on (1) the conceptual framework for appropriate evaluation of kidney dysfunction within the context of clinical trajectories in advanced heart failure, including in the consideration of advanced heart failure therapies; (2) preoperative, perioperative, and postoperative approaches to evaluation and management of kidney disease for advanced surgical therapies (durable left ventricular assist device/heart transplantation) and kidney replacement therapies; and (3) the key concepts in palliative care and decision-making processes unique to individuals with concomitant advanced heart failure and kidney disease.

Shared genetic effect of kidney function on bipolar and major depressive disorders: a large-scale genome-wide cross-trait analysis.

BACKGROUND: Epidemiological studies have revealed a significant association between impaired kidney function and certain mental disorders, particularly bipolar disorder (BIP) and major depressive disorder (MDD). However, the evidence regarding shared genetics and causality is limited due to residual confounding and reverse causation. METHODS: In this study, we conducted a large-scale genome-wide cross-trait association study to investigate the genetic overlap between 5 kidney function biomarkers (eGFRcrea, eGFRcys, blood urea nitrogen (BUN), serum urate, and UACR) and 2 mental disorders (MDD, BIP). Summary-level data of European ancestry were extracted from UK Biobank, Chronic Kidney Disease Genetics Consortium, and Psychiatric Genomics Consortium. RESULTS: Using LD score regression, we found moderate but significant genetic correlations between kidney function biomarker traits on BIP and MDD. Cross-trait meta-analysis identified 1 to 19 independent significant loci that were found shared among 10 pairs of 5 kidney function biomarkers traits and 2 mental disorders. Among them, 3 novel genes: SUFU, IBSP, and PTPRJ, were also identified in transcriptome-wide association study analysis (TWAS), most of which were observed in the nervous and digestive systems (FDR < 0.05). Pathway analysis showed the immune system could play a role between kidney function biomarkers and mental disorders. Bidirectional mendelian randomization analysis suggested a potential causal relationship of kidney function biomarkers on BIP and MDD. CONCLUSIONS: In conclusion, the study demonstrated that both BIP and MDD shared genetic architecture with kidney function biomarkers, providing new insights into their genetic architectures and suggesting that larger GWASs are warranted.

Renal Denervation to Treat Heart Failure.

Heart failure (HF) is a global pandemic with a poor prognosis after hospitalization. Despite HF syndrome complexities, evidence of significant sympathetic overactivity in the manifestation and progression of HF is universally accepted. Confirmation of this dogma is observed in guideline-directed use of neurohormonal pharmacotherapies as a standard of care in HF. Despite reductions in morbidity and mortality, a growing patient population is resistant to these medications, while off-target side effects lead to dismal patient adherence to lifelong drug regimens. Novel therapeutic strategies, devoid of these limitations, are necessary to attenuate the progression of HF pathophysiology while continuing to reduce morbidity and mortality. Renal denervation is an endovascular procedure, whereby the ablation of renal nerves results in reduced renal afferent and efferent sympathetic nerve activity in the kidney and globally. In this review, we discuss the current state of preclinical and clinical research related to renal sympathetic denervation to treat HF.

Function of Renal Nerves in Kidney Physiology and Pathophysiology.

Renal sympathetic (efferent) nerves play an important role in the regulation of renal function, including glomerular filtration, sodium reabsorption, and renin release. The kidney is also innervated by sensory (afferent) nerves that relay information to the brain to modulate sympathetic outflow. Hypertension and other cardiometabolic diseases are linked to overactivity of renal sympathetic and sensory nerves, but our mechanistic understanding of these relationships is limited. Clinical trials of catheter-based renal nerve ablation to treat hypertension have yielded promising results. Therefore, a greater understanding of how renal nerves control the kidney under physiological and pathophysiological conditions is needed. In this review, we provide an overview of the current knowledge of the anatomy of efferent and afferent renal nerves and their functions in normal and pathophysiological conditions. We also suggest further avenues of research for development of novel therapies targeting the renal nerves.

Association of plasma ceramide with decline in kidney function in patients with type 2 diabetes.

Circulating ceramide levels are dysregulated in kidney disease. However, their associations with rapid decline in kidney function (RDKF) and end-stage kidney disease (ESKD) in patients with type 2 diabetes (T2D) are unknown. In this prospective study of 1746 T2D participants, we examined the association of plasma ceramide Cer16:0, Cer18:0, Cer24:0, and Cer24:1 with RDKF, defined as an estimated glomerular filtration rate (eGFR) decline of 5 ml/min/1.73 m2 per year or greater, and ESKD defined as eGFR <15/min/1.73 m2 for at least 3 months, on dialysis or renal death at follow-up. During a median follow-up period of 7.7 years, 197 patients experienced RDKF. Ceramide Cer24:0 (odds ratio [OR] = 0.71, 95% CI 0.56-0.90) and ratios Cer16:0/Cer24:0 (OR = 3.54 [1.70-7.35]), Cer18:0/Cer24:0 (OR = 1.89 [1.10-3.25]), and Cer24:1/Cer24:0 (OR = 4.01 [1.93-8.31]) significantly associated with RDKF in multivariable analysis; 124 patients developed ESKD. The ratios Cer16:0/Cer24:0 (hazard ratio [HR] = 3.10 [1.44-6.64]) and Cer24:1/Cer24:0 (HR = 4.66 [1.93-11.24]) significantly associated with a higher risk of ESKD. The Cer24:1/Cer24:0 ratio improved risk discrimination for ESKD beyond traditional risk factors by small but statistically significant margin (Harrell C-index difference: 0.01; P = 0.022). A high ceramide risk score also associated with RDKF (OR = 2.28 [1.26-4.13]) compared to lower risk score. In conclusion, specific ceramide levels and their ratios are associated with RDKF and conferred an increased risk of ESKD, independently of traditional risk factors, including baseline renal functions in patients with T2D.

Non-adherence to cardiometabolic medication as assessed by LC-MS/MS in urine and its association with kidney and cardiovascular outcomes in type 2 diabetes mellitus.

AIMS/HYPOTHESIS: Non-adherence to medication is a frequent barrier in the treatment of patients with type 2 diabetes mellitus, potentially limiting the effectiveness of evidence-based treatments. Previous studies have mostly relied on indirect adherence measures to analyse outcomes based on adherence. The aim of this study was to use LC-MS/MS in urine-a non-invasive, direct and objective measure-to assess non-adherence to cardiometabolic drugs and analyse its association with kidney and cardiovascular outcomes. METHODS: This cohort study includes 1125 participants from the PROVALID study, which follows patients with type 2 diabetes mellitus at the primary care level. Baseline urine samples were tested for 79 cardiometabolic drugs and metabolites thereof via LC-MS/MS. An individual was classified as totally adherent if markers for all drugs were detected, partially non-adherent when at least one marker for one drug was detected, and totally non-adherent if no markers for any drugs were detected. Non-adherence was then analysed in the context of cardiovascular (composite of myocardial infarction, stroke and cardiovascular death) and kidney (composite of sustained 40% decline in eGFR, sustained progression of albuminuria, kidney replacement therapy and death from kidney failure) outcomes. RESULTS: Of the participants, 56.3% were totally adherent, 42.0% were partially non-adherent, and 1.7% were totally non-adherent to screened cardiometabolic drugs. Adherence was highest to antiplatelet and glucose-lowering agents and lowest to lipid-lowering agents. Over a median (IQR) follow-up time of 5.10 (4.12-6.12) years, worse cardiovascular outcomes were observed with non-adherence to antiplatelet drugs (HR 10.13 [95% CI 3.06, 33.56]) and worse kidney outcomes were observed with non-adherence to antihypertensive drugs (HR 1.98 [95% CI 1.37, 2.86]). CONCLUSIONS/INTERPRETATION: This analysis shows that non-adherence to cardiometabolic drug regimens is common in type 2 diabetes mellitus and negatively affects kidney and cardiovascular outcomes.

Mitochondrial dysfunction in the pathophysiology of renal diseases.

Mitochondria are essential organelles in the human body, serving as the metabolic factory of the whole organism. When mitochondria are dysfunctional, it can affect all organs of the body. The kidney is rich in mitochondria, and its function is closely related to the development of kidney diseases. Studying the relationship between mitochondria and kidney disease progression is of great interest. In the past decade, scientists have made inspiring progress in investigating the role of mitochondria in the pathophysiology of renal diseases. This article discusses various mechanisms for maintaining mitochondrial quality, including mitochondrial energetics, mitochondrial biogenesis, mitochondrial dynamics, mitochondrial DNA repair, mitochondrial proteolysis and the unfolded protein response, mitochondrial autophagy, mitochondria-derived vesicles, and mitocytosis. The article also highlights the cross talk between mitochondria and other organelles, with a focus on kidney diseases. Finally, the article concludes with an overview of mitochondria-related clinical research.

Chronic mistimed feeding results in renal fibrosis and disrupted circadian blood pressure rhythms.

Circadian disruption is a disturbance in biological timing, which can occur within or between different organizational levels, ranging from molecular rhythms within specific cells to the misalignment of behavioral and environmental cycles. Previous work from our group showed that less than 1 wk of food restriction to the light (inactive) period is sufficient to invert diurnal blood pressure rhythms in mice. However, kidney excretory rhythms and functions remained aligned with the light-dark cycle. Shift workers have an increased risk of cardiovascular disease that may different between sexes and often have irregular mealtimes, making the possibility of mistimed feeding as a potential contributor to the development of kidney disease. Thus, we hypothesized that chronic mistimed food intake would result in adverse cardiorenal effects, with sex differences in severity. Here, we show that chronic circadian disruption via mistimed feeding results in renal fibrosis and aortic stiffness in a sex-dependent manner. Our results indicate the importance of meal timing for the maintenance of blood pressure rhythms and kidney function, particularly in males. Our results also demonstrate that females are better able to acclimate to circadian-related behavioral change. NEW & NOTEWORTHY Circadian disruption through mistimed feeding resulted in nondipping blood pressure, renal fibrosis, and arterial stiffness that were less severe in females versus males. Mice fed exclusively during the daytime maintain their circadian rhythms of locomotor activity regardless of their loss of blood pressure rhythms. Although these mice ate less food, they maintained body weight, suggesting inefficiencies in overall metabolism. These findings demonstrate the importance of maintaining optimal food intake patterns to prevent cardiorenal pathophysiology.

Animal models to study cognitive impairment of chronic kidney disease.

Mild cognitive impairment (MCI) is common in people with chronic kidney disease (CKD), and its prevalence increases with progressive loss of kidney function. MCI is characterized by a decline in cognitive performance greater than expected for an individual age and education level but with minimal impairment of instrumental activities of daily living. Deterioration can affect one or several cognitive domains (attention, memory, executive functions, language, and perceptual motor or social cognition). Given the increasing prevalence of kidney disease, more and more people with CKD will also develop MCI causing an enormous disease burden for these individuals, their relatives, and society. However, the underlying pathomechanisms are poorly understood, and current therapies mostly aim at supporting patients in their daily lives. This illustrates the urgent need to elucidate the pathogenesis and potential therapeutic targets and test novel therapies in appropriate preclinical models. Here, we will outline the necessary criteria for experimental modeling of cognitive disorders in CKD. We discuss the use of mice, rats, and zebrafish as model systems and present valuable techniques through which kidney function and cognitive impairment can be assessed in this setting. Our objective is to enable researchers to overcome hurdles and accelerate preclinical research aimed at improving the therapy of people with CKD and MCI.

Resting-state MRI reveals spontaneous physiological fluctuations in the kidney and tracks diabetic nephropathy in rats.

The kidneys maintain fluid-electrolyte balance and excrete waste in the presence of constant fluctuations in plasma volume and systemic blood pressure. The kidneys perform these functions to control capillary perfusion and glomerular filtration by modulating the mechanisms of autoregulation. An effect of these modulations are spontaneous, natural fluctuations in glomerular perfusion. Numerous other mechanisms can lead to fluctuations in perfusion and flow. The ability to monitor these spontaneous physiological fluctuations in vivo could facilitate the early detection of kidney disease. The goal of this work was to investigate the use of resting-state magnetic resonance imaging (rsMRI) to detect spontaneous physiological fluctuations in the kidney. We performed rsMRI of rat kidneys in vivo over 10 min, applying motion correction to resolve time series in each voxel. We observed spatially variable, spontaneous fluctuations in rsMRI signal between 0 and 0.3 Hz, in frequency bands associated with autoregulatory mechanisms. We further applied rsMRI to investigate changes in these fluctuations in a rat model of diabetic nephropathy. Spectral analysis was performed on time series of rsMRI signals in the kidney cortex and medulla. The power from spectra in specific frequency bands from the cortex correlated with severity of glomerular pathology caused by diabetic nephropathy. Finally, we investigated the feasibility of using rsMRI of the human kidney in two participants, observing the presence of similar, spatially variable fluctuations. This approach may enable a range of preclinical and clinical investigations of kidney function and facilitate the development of new therapies to improve outcomes in patients with kidney disease.NEW & NOTEWORTHY This work demonstrates the development and use of resting-state MRI to detect low-frequency, spontaneous physiological fluctuations in the kidney consistent with previously observed fluctuations in perfusion and potentially due to autoregulatory function. These fluctuations are detectable in rat and human kidneys, and the power of these fluctuations is affected by diabetic nephropathy in rats.

Sex-disaggregated analysis of acute kidney injury in hospitalized children with sickle cell anemia in Uganda.

A growing body of research is categorizing sex differences in both sickle cell anemia (SCA) and acute kidney injury (AKI); however, most of this work is being conducted in high-resource settings. Here, we evaluated risk factors and clinical parameters associated with AKI and AKI severity, stratified by sex, in a cohort of children hospitalized with SCA and vaso-occlusive pain crisis (VOC). The purpose of this study was to explore sex disparities in a high-risk, vulnerable population. This study was a secondary analysis of data collected from a cohort of Ugandan children between 2 and 18 yr of age prospectively enrolled. A total of 185 children were enrolled in the primary study; 41.6% were female and 58.4% were male, with a median age of 8.9 yr. Incident or worsening AKI (P = 0.026) occurred more frequently in female compared with male children, despite no differences in AKI on admission. Female children also had altered markers of renal function including higher creatinine levels at admission (P = 0.03), higher peak creatinine (P = 0.006), and higher urine neutrophil gelatinase-associated lipocalin (NGAL) at admission (P = 0.003) compared with male children. Female children had elevated total (P = 0.045) and conjugated bilirubin at admission (P = 0.02) compared with male children and higher rates of hematuria at admission (P = 0.004). Here, we report sex differences in AKI in children with SCA and VOC, including increased incidence and worsening of AKI in female pediatric patients, in association with an increase in biological indicators of poor renal function including creatinine, estimated glomerular filtration rate, and NGAL.NEW & NOTEWORTHY In this study, we report an increased risk of developing acute kidney injury (AKI) during hospitalization, worsening AKI, and death among females with sickle cell anemia (SCA) hospitalized with an acute pain crisis compared with males. The sex differences in AKI were not explained by socioeconomic differences, severity of pain, or disease severity among females compared with males. Together, these data suggest that female children with SCA may be at increased risk of AKI.

Parental obesity predisposes offspring to kidney dysfunction and increased susceptibility to ischemia-reperfusion injury in a sex-dependent manner.

Although obesity is recognized as a risk factor for cardiorenal and metabolic diseases, the impact of parental obesity on the susceptibility of their offspring to renal injury at adulthood is unknown. We examined the impact of parental obesity on offspring kidney function, morphology, and markers of kidney damage after acute kidney injury (AKI). Offspring from normal (N) diet-fed C57BL/6J parents were fed either N (NN) or a high-fat (H) diet (NH) from weaning until adulthood. Offspring from obese H diet-fed parents were fed N (HN) or H diet (HH) after weaning. All offspring groups were submitted to bilateral AKI by clamping the left and right renal pedicles for 30 min. Compared with male NH and NN offspring from lean parents, male HH and HN offspring from obese parents exhibited higher kidney injury markers such as urinary, renal osteopontin, plasma creatinine, urinary albumin excretion, and neutrophil gelatinase-associated lipocalin (NGAL) levels, and worse histological injury score at 22 wk of age. Only albumin excretion and NGAL were elevated in female HH offspring from obese parents compared with lean and obese offspring from lean parents. We also found an increased mortality rate and worse kidney injury scores after AKI in male offspring from obese parents, regardless of the diet consumed after weaning. Female offspring were protected from major kidney injury after AKI. These results indicate that parental obesity leads to increased kidney injury in their offspring after ischemia-reperfusion in a sex-dependent manner, even when their offspring remain lean.NEW & NOTEWORTHY Offspring from obese parents are more susceptible to kidney injury and worse outcomes following an acute ischemia-reperfusion insult. Male, but not female, offspring from obese parents exhibit increased blood pressure early in life. Female offspring are partially protected against major kidney injury induced by ischemia-reperfusion.

Establishment and characterization of a mouse model for studying kidney repair in diabetes.

The prognosis of acute kidney injury (AKI) is markedly worse in patients with diabetes. Diabetes not only exaggerates the severity of AKI but also prevent kidney repair or recovery from AKI. Little is known about the cellular and molecular basis of defective kidney repair in diabetes. One obstacle in studying kidney repair in diabetes is the lack of suitable animal models. Specifically, diabetes increases AKI severity, making it difficult to induce the same level of AKI in diabetic and nondiabetic animals to compare their kidney repair. Here, we have identified a time window of 4 days immediately after the completion of streptozotocin (STZ) treatment in mice when blood glucose has yet to rise. Within this time window, renal ischemia-reperfusion injury (IRI) induced the same level of AKI in STZ-treated mice [127.2 ± 12.82 mg/dL blood urea nitrogen (BUN), 2.275 ± 0.4728 serum creatinine] and vehicle solution-treated mice (128.6 ± 11.83 mg/dL BUN, 2.087 ± 0.4748 mg/dL serum creatinine]. By days 5-6, the post-AKI kidney entered into the phase of kidney repair when diabetic hyperglycemia started in STZ-treated mice, providing the opportunity to study the effect of diabetes on kidney repair without affecting initial AKI. In this model, kidney repair was indeed impaired by diabetes (116.5 ± 8.052 mg/dL BUN and 1.382 ± 0.2732 mg/dL serum creatinine in IR + vehicle group; 136.6 ± 8.740 mg/dL BUN and 1.916 ± 0.3756 mg/dL serum creatinine in IR + STZ group). The impairment was associated with decreased tubular cell proliferation and increased tubular cell senescence, peritubular capillary (PTC) rarefaction, inflammation, and 40.90% more interstitial fibrosis.NEW & NOTEWORTHY Little is known about the cellular and molecular basis of defective kidney repair in diabetes. One obstacle in studying kidney repair in diabetes is the lack of suitable animal models. Here, we report a mouse model to investigate the effect of diabetes on kidney repair without affecting initial injury and found that the repair defect is associated with decreased renal tubular cell proliferation and increased tubular cell senescence, PTC rarefaction, inflammation, and interstitial fibrosis.

Chronic infusion of the tryptophan metabolite kynurenine increases mean arterial pressure in male Sprague-Dawley rats.

Chronic kidney disease is the loss of renal function that can occur from aging or through a myriad of other disease states. Rising serum concentrations of kynurenine, a tryptophan metabolite, have been shown to correlate with increasing severity of chronic kidney disease. This study used chronic intravenous infusion in conscious male Sprague-Dawley rats to test the hypothesis that kynurenine can induce renal damage and promote alterations in blood pressure, heart rate, and decreased renal function. We found that kynurenine infusion increased mean arterial pressure, increased the maximum and minimum range of heart rate, decreased glomerular filtration rate, and induced kidney damage in a dose-dependent manner. This study shows that kynurenine infusion can promote kidney disease in healthy, young rats, implying that the increase in kynurenine levels associated with chronic kidney disease may establish a feed-forward mechanism that exacerbates the loss of renal function.NEW & NOTEWORTHY In humans, an elevated serum concentration of kynurenine has long been associated with negative outcomes in various disease states as well as in aging. However, it has been unknown whether these increased kynurenine levels are mediating the disorders or simply associated with them. This study shows that chronically infusing kynurenine can contribute to the development of hypertension and kidney impairment. The mechanism of this action remains to be determined in future studies.

Impaired distal renal potassium handling in streptozotocin-induced diabetic mice.

Diabetes is closely associated with K+ disturbances during disease progression and treatment. However, it remains unclear whether K+ imbalance occurs in diabetes with normal kidney function. In this study, we examined the effects of dietary K+ intake on systemic K+ balance and renal K+ handling in streptozotocin (STZ)-induced diabetic mice. The control and STZ mice were fed low or high K+ diet for 7 days to investigate the role of dietary K+ intake in renal K+ excretion and K+ homeostasis and to explore the underlying mechanism by evaluating K+ secretion-related transport proteins in distal nephrons. K+-deficient diet caused excessive urinary K+ loss, decreased daily K+ balance, and led to severe hypokalemia in STZ mice compared with control mice. In contrast, STZ mice showed an increased daily K+ balance and elevated plasma K+ level under K+-loading conditions. Dysregulation of the NaCl cotransporter (NCC), epithelial Na+ channel (ENaC), and renal outer medullary K+ channel (ROMK) was observed in diabetic mice fed either low or high K+ diet. Moreover, amiloride treatment reduced urinary K+ excretion and corrected hypokalemia in K+-restricted STZ mice. On the other hand, inhibition of SGLT2 by dapagliflozin promoted urinary K+ excretion and normalized plasma K+ levels in K+-supplemented STZ mice, at least partly by increasing ENaC activity. We conclude that STZ mice exhibited abnormal K+ balance and impaired renal K+ handling under either low or high K+ diet, which could be primarily attributed to the dysfunction of ENaC-dependent renal K+ excretion pathway, despite the possible role of NCC.NEW & NOTEWORTHY Neither low dietary K+ intake nor high dietary K+ intake effectively modulates renal K+ excretion and K+ homeostasis in STZ mice, which is closely related to the abnormality of ENaC expression and activity. SGLT2 inhibitor increases urinary K+ excretion and reduces plasma K+ level in STZ mice under high dietary K+ intake, an effect that may be partly due to the upregulation of ENaC activity.

Predicting sex differences in the effects of diuretics in renal epithelial transport during angiotensin II-induced hypertension.

Chronic angiotensin II (ANG II) infusion is an experimental model that induces hypertension in rodents. The natriuresis, diuresis, and blood pressure responses differ between males and females. This is perhaps not unexpected, given the rodent kidney, which plays a key role in blood pressure regulation, exhibits marked sex differences. Under normotensive conditions, compared with males, the female rat nephron exhibits lower Na+/H+ exchanger 3 (NHE3) activity along the proximal tubule but higher Na+ transporter activities along the distal segments. ANG II infusion-induced hypertension induces a pressure natriuretic response that reduces NHE3 activity and shifts Na+ transport capacity downstream. The goals of this study were to apply a computational model of epithelial transport along a rat nephron 1) to understand how a 14-day ANG II infusion impacts segmental electrolyte transport in male and female rat nephrons and 2) to identify and explain any sex differences in the effects of loop diuretics, thiazide diuretics, and K+-sparing diuretics. Model simulations suggest that the NHE3 downregulation in the proximal tubule is a major contributor to natriuresis and diuresis in hypertension, with the effects stronger in males. All three diuretics are predicted to induce stronger natriuretic and diuretic effects under hypertension compared with normotension, with relative increases in sodium excretion higher in hypertensive females than in males. The stronger natriuretic responses can be explained by the downstream shift of Na+ transport load in hypertension and by the larger distal transport load in females, both of which limit the ability of the distal segments to further elevate their Na+ transport.NEW & NOTEWORTHY Sex differences in the prevalence of hypertension are found in human and animal models. The kidney, which regulates blood pressure, exhibits sex differences in morphology, hemodynamics, and membrane transporter distributions. This computational modeling study provides insights into how the sexually dimorphic responses to a 14-day angiotensin II infusion differentially impact segmental electrolyte transport in rats. Simulations of diuretic administration explain how the natriuretic and diuretic effects differ between normotension and hypertension and between the sexes.