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Kidney International Mar 2022An increase of glomerular filtration rate (GFR) is a common observation in early diabetes and is considered a key risk factor for subsequent kidney injury. However, the...
An increase of glomerular filtration rate (GFR) is a common observation in early diabetes and is considered a key risk factor for subsequent kidney injury. However, the mechanisms underlying diabetic hyperfiltration have not been fully clarified. Here, we tested the hypothesis that macula densa neuronal nitric oxide synthase (NOS1) is upregulated via sodium glucose cotransporter type 1 (SGLT1) in diabetes, which then inhibits tubuloglomerular feedback (TGF) promoting glomerular hyperfiltration. Therefore, we examined changes in cortical NOS1 expression and phosphorylation, nitric oxide production in the macula densa, TGF response, and GFR during the early stage of insulin-deficient (Akita) diabetes in wild-type and macula densa-specific NOS1 knockout mice. A set of sophisticated techniques including microperfusion of juxtaglomerular apparatus in vitro, micropuncture of kidney tubules in vivo, and clearance kinetics of plasma fluorescent-sinistrin were employed. Complementary studies tested the role of SGLT1 in SGLT1 knockout mice and explored NOS1 expression and phosphorylation in kidney biopsies of cadaveric donors. Diabetic mice had upregulated macula densa NOS1, inhibited TGF and elevated GFR. Macula densa-selective NOS1 knockout attenuated the diabetes-induced TGF inhibition and GFR elevation. Additionally, deletion of SGLT1 prevented the upregulation of macula densa NOS1 and attenuated inhibition of TGF in diabetic mice. Furthermore, the expression and phosphorylation levels of NOS1 were increased in cadaveric kidneys of diabetics and positively correlated with blood glucose as well as estimated GFR in the donors. Thus, our findings demonstrate that the macula densa SGLT1-NOS1-TGF pathway plays a crucial role in the control of GFR in diabetes.
Topics: Animals; Diabetes Mellitus, Experimental; Feedback; Glomerular Filtration Rate; Kidney Glomerulus; Kidney Tubules; Mice; Nitric Oxide; Nitric Oxide Synthase Type I; Sodium-Glucose Transporter 1
PubMed: 34843754
DOI: 10.1016/j.kint.2021.10.037 -
American Journal of Physiology. Renal... Dec 2021Macula densa (MD) cells, a chief sensory cell type in the nephron, are endowed with unique microanatomic features including a high density of protein synthetic...
Macula densa (MD) cells, a chief sensory cell type in the nephron, are endowed with unique microanatomic features including a high density of protein synthetic organelles and secretory vesicles in basal cell processes ("maculapodia") that suggest a so far unknown high rate of MD protein synthesis. This study aimed to explore the rate and regulation of MD protein synthesis and their effects on glomerular function using novel transgenic mouse models, newly established fluorescence cell biology techniques, and intravital microscopy. Sox2-tdTomato kidney tissue sections and an -propargyl puromycin incorporation-based fluorescence imaging assay showed that MD cells have the highest level of protein synthesis within the kidney cortex followed by intercalated cells and podocytes. Genetic gain of function of mammalian target of rapamycin (mTOR) signaling specifically in MD cells (in MD-mTOR mice) or their physiological activation by low-salt diet resulted in further significant increases in the synthesis of MD proteins. Specifically, these included both classic and recently identified MD-specific proteins such as cyclooxygenase 2, microsomal prostaglandin E synthase 1, and pappalysin 2. Intravital imaging of the kidney using multiphoton microscopy showed significant increases in afferent and efferent arteriole and glomerular capillary diameters and blood flow in MD-mTOR mice coupled with an elevated glomerular filtration rate. The presently identified high rate of MD protein synthesis that is regulated by mTOR signaling is a novel component of the physiological activation and glomerular hemodynamic regulatory functions of MD cells that remains to be fully characterized. This study discovered the high rate of protein synthesis in macula densa (MD) cells by applying direct imaging techniques with single cell resolution. Physiological activation and mammalian target of rapamycin signaling played important regulatory roles in this process. This new feature is a novel component of the tubuloglomerular cross talk and glomerular hemodynamic regulatory functions of MD cells. Future work is needed to elucidate the nature and (patho)physiological role of the specific proteins synthesized by MD cells.
Topics: Animals; Autocrine Communication; Diet, Sodium-Restricted; Glomerular Filtration Rate; Green Fluorescent Proteins; Humans; Intravital Microscopy; Juxtaglomerular Apparatus; Luminescent Proteins; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Fluorescence, Multiphoton; Nitric Oxide Synthase Type I; Paracrine Communication; Protein Biosynthesis; Renin; Signal Transduction; Sodium, Dietary; TOR Serine-Threonine Kinases; Tuberous Sclerosis Complex 2 Protein; Red Fluorescent Protein; Mice
PubMed: 34693742
DOI: 10.1152/ajprenal.00222.2021 -
Physiological Reports Sep 2021Olfactory receptor 78 (Olfr78) is a G protein-coupled receptor (GPCR) that is expressed in the juxtaglomerular apparatus (JGA) of the kidney as well as the peripheral...
Olfactory receptor 78 (Olfr78) is a G protein-coupled receptor (GPCR) that is expressed in the juxtaglomerular apparatus (JGA) of the kidney as well as the peripheral vasculature, and is activated by gut microbial metabolites. We previously reported that Olfr78 plays a role in renin secretion in isolated glomeruli, and that Olfr78 knockout (KO) mice have lower plasma renin activity. We also noted that in anesthetized mice, Olfr78KO appeared to be hypotensive. In this study, we used radiotelemetry to determine the role of Olfr78 in chronic blood pressure regulation. We found that the blood pressure of Olfr78KO mice is not significantly different than that of their WT counterparts at baseline, or on high- or low-salt diets. However, Olfr78KO mice have depressed heart rates on high-salt diets. We also report that Olfr78KO mice have lower renin protein levels associated with glomeruli. Finally, we developed a mouse where Olfr78 was selectively knocked out in the JGA, which phenocopied the lower renin association findings. In sum, these experiments suggest that Olfr78 modulates renin, but does not play an active role in blood pressure regulation at baseline, and is more likely activated by high levels of short chain fatty acids or hypotensive events. This study provides important context to our knowledge of Olfr78 in BP regulation.
Topics: Animals; Blood Pressure; Female; Hypertension; Kidney; Male; Mice; Mice, Inbred C57BL; Receptors, Odorant; Renin
PubMed: 34549531
DOI: 10.14814/phy2.15017 -
Urology Dec 2021
Topics: Adult; Female; Humans; Hypertension; Juxtaglomerular Apparatus; Kidney Neoplasms
PubMed: 34536412
DOI: 10.1016/j.urology.2021.08.039 -
Journal of the American Society of... Oct 2021Regulation of renal hemodynamics and BP via tubuloglomerular feedback (TGF) may be an important adaptive mechanism during pregnancy. Because the β-splice variant of...
BACKGROUND
Regulation of renal hemodynamics and BP via tubuloglomerular feedback (TGF) may be an important adaptive mechanism during pregnancy. Because the β-splice variant of nitric oxide synthase 1 (NOS1β) in the macula densa is a primary modulator of TGF, we evaluated its role in normal pregnancy and gestational hypertension in a mouse model. We hypothesized that pregnancy upregulates NOS1β in the macula densa, thus blunting TGF, allowing the GFR to increase and BP to decrease.
METHODS
We used sophisticated techniques, including microperfusion of juxtaglomerular apparatus , micropuncture of renal tubules , clearance kinetics of plasma FITC-sinistrin, and radiotelemetry BP monitoring, to determine the effects of normal pregnancy or reduced uterine perfusion pressure (RUPP) on macula densa NOS1β/NO levels, TGF responsiveness, GFR, and BP in wild-type and macula densa-specific NOS1 knockout (MD-NOS1KO) mice.
RESULTS
Macula densa NOS1β was upregulated during pregnancy, resulting in blunted TGF, increased GFR, and decreased BP. These pregnancy-induced changes in TGF and GFR were largely diminished, with a significant rise in BP, in MD-NOS1KO mice. In addition, RUPP resulted in a downregulation in macula densa NOS1β, enhanced TGF, decreased GFR, and hypertension. The superimposition of RUPP into MD-NOS1KO mice only caused a modest further alteration in TGF and its associated changes in GFR and BP. Finally, in African green monkeys, renal cortical NOS1β expression increased in normotensive pregnancies, but decreased in spontaneous gestational hypertensive pregnancies.
CONCLUSIONS
Macula densa NOS1β plays a critical role in the control of renal hemodynamics and BP during pregnancy.
Topics: Animals; Arterial Pressure; Chlorocebus aethiops; Feedback, Physiological; Female; Glomerular Filtration Rate; Hypertension, Pregnancy-Induced; Isoenzymes; Kidney Glomerulus; Kidney Tubules, Distal; Mice; Mice, Knockout; Nitric Oxide Synthase Type I; Pregnancy; Renal Circulation; Up-Regulation; Uterus
PubMed: 34127535
DOI: 10.1681/ASN.2020070969 -
The Journal of Clinical Investigation Jun 2021Skeletal muscle wasting is commonly associated with chronic kidney disease (CKD), resulting in increased morbidity and mortality. However, the link between kidney and...
Skeletal muscle wasting is commonly associated with chronic kidney disease (CKD), resulting in increased morbidity and mortality. However, the link between kidney and muscle function remains poorly understood. Here, we took a complementary interorgan approach to investigate skeletal muscle wasting in CKD. We identified increased production and elevated blood levels of soluble pro-cachectic factors, including activin A, directly linking experimental and human CKD to skeletal muscle wasting programs. Single-cell sequencing data identified the expression of activin A in specific kidney cell populations of fibroblasts and cells of the juxtaglomerular apparatus. We propose that persistent and increased kidney production of pro-cachectic factors, combined with a lack of kidney clearance, facilitates a vicious kidney/muscle signaling cycle, leading to exacerbated blood accumulation and, thereby, skeletal muscle wasting. Systemic pharmacological blockade of activin A using soluble activin receptor type IIB ligand trap as well as muscle-specific adeno-associated virus-mediated downregulation of its receptor ACVR2A/B prevented muscle wasting in different mouse models of experimental CKD, suggesting that activin A is a key factor in CKD-induced cachexia. In summary, we uncovered a crosstalk between kidney and muscle and propose modulation of activin signaling as a potential therapeutic strategy for skeletal muscle wasting in CKD.
Topics: Activin Receptors, Type II; Activins; Animals; Cachexia; Disease Models, Animal; HEK293 Cells; Humans; Mice; Mice, Knockout; Muscle, Skeletal; Muscular Atrophy; Renal Insufficiency, Chronic; Wasting Syndrome
PubMed: 34060483
DOI: 10.1172/JCI135821 -
Urology Oct 2021Hypertension is often the primary presenting symptom of multiple renal pathologies. Overactivity of the Renin-Angiotensin-Aldosterone-System (RAAS) is a common cause and...
Hypertension is often the primary presenting symptom of multiple renal pathologies. Overactivity of the Renin-Angiotensin-Aldosterone-System (RAAS) is a common cause and usually results from an induced physiologic response. However, conditions do exist that involve autonomous renin production. Juxtaglomerular cell tumors (JGCT), or reninomas, are renal lesions that cause refractory hypertension via this mechanism. Symptoms and lab abnormalities usually subside with surgical resection of these tumors. Here, we present a case of a 13-year old female with uncontrolled hypertension secondary to reninoma treated with partial nephrectomy, with focus on initial presentation, diagnostic evaluation, and surgical management of this uncommon tumor.
Topics: Adolescent; Female; Humans; Hypertension; Juxtaglomerular Apparatus; Kidney Neoplasms; Nephrectomy
PubMed: 34058239
DOI: 10.1016/j.urology.2021.05.030 -
BioMed Research International 2021Gitelman syndrome (GS) is an autosomal recessive inherited salt-losing renal tubular disease, which is caused by a pathogenic mutation of encoding thiazide-sensitive...
Gitelman syndrome (GS) is an autosomal recessive inherited salt-losing renal tubular disease, which is caused by a pathogenic mutation of encoding thiazide-sensitive Na-Cl cotransporter, which leads to disturbance of sodium and chlorine reabsorption in renal distal convoluted tubules, resulting in phenotypes such as hypovolemia, renin angiotensin aldosterone system (RAAS) activation, hypokalemia, and metabolic alkalosis. In this study, two GS families with proteinuria or Hashimoto's thyroiditis were analyzed for genetic-phenotypic association. Sanger sequencing revealed that two probands carried compound heterozygous mutations, and proband A carried two pathogenic mutations: missense mutation Arg83Gln, splicing mutation, or frameshift mutation NC_000016.10:g.56872655_56872667 (gcggacatttttg>accgaaaatttt) in exon 8. Proband B carries two missense mutations: novel Asp839Val and Arg904Gln. Both probands manifested hypokalemia, hypomagnesemia, hypocalcinuria, metabolic alkalosis, and RAAS activation; in addition, the proband A exhibited decreased urinary chloride, phosphorus, and increased magnesium ions excretion, complicated with Hashimoto's Thyroiditis, while the proband B exhibited enhanced urine sodium excretion and proteinuria. The older sister of proband B with GS also had Hashimoto's thyroiditis. Electron microscopy revealed swelling and vacuolar degeneration of glomerular epithelial cells, diffuse proliferation of mesangial cells and matrix, accompanied by a small amount of low-density electron-dense deposition, and segmental fusion of epithelial cell foot processes in proband B. Light microscopy showed mild mesangial hyperplasia in the focal segment of the glomerulus, hyperplasia, and hypertrophy of juxtaglomerular apparatus cells, mild renal tubulointerstitial lesions, and one glomerular sclerosis. So, long-term hypokalemia of GS can cause kidney damage and may also be susceptible to thyroid disease.
Topics: Adult; Female; Genetic Predisposition to Disease; Gitelman Syndrome; Hashimoto Disease; Heterozygote; Humans; Hypokalemia; Kidney Glomerulus; Magnesium; Male; Mutation; Mutation, Missense; Pedigree; Phenotype; Proteinuria; Receptors, Drug; Sodium Chloride Symporters; Solute Carrier Family 12, Member 3
PubMed: 34046503
DOI: 10.1155/2021/9973161 -
Cardiorenal Medicine 2021Clinical guidelines include diuretics for the treatment of heart failure (HF), not to decrease mortality but to decrease symptoms and hospitalizations. More attention... (Review)
Review
Clinical guidelines include diuretics for the treatment of heart failure (HF), not to decrease mortality but to decrease symptoms and hospitalizations. More attention has been paid to the worse outcomes, including mortality, associated with continual diuretic therapy due to hypochloremia. Studies have revealed a pivotal role for serum chloride in the pathophysiology of HF and is now a target of treatment to decrease mortality. The prognostic value of serum chloride in HF has been the subject of much attention. Mechanistically, the macula densa, a region in the renal juxtaglomerular apparatus, relies on chloride levels to sense salt and volume status. The recent discovery of with-no-lysine (K) (WNK) protein kinase as an intracellular chloride sensor sheds light on the possible reason of diuretic resistance in HF. The action of chloride on WNKs results in the upregulation of the sodium-potassium-chloride cotransporter and sodium-chloride cotransporter receptors, which could lead to increased electrolyte and fluid reabsorption. Genetic studies have revealed that a variant of a voltage-sensitive chloride channel (CLCNKA) gene leads to almost a 50% decrease in current amplitude and function of the renal chloride channel. This variant increases the risk of HF. Several trials exploring the prognostic value of chloride in both acute and chronic HF have shown mostly positive results, some even suggesting a stronger role than sodium. However, so far, interventional trials exploring serum chloride as a therapeutic target have been largely inconclusive. This study is a review of the pathophysiologic effects of hypochloremia in HF, the genetics of chloride channels, and clinical trials that are underway to investigate novel approaches to HF management.
Topics: Chlorides; Diuretics; Heart Failure; Humans; Sodium; Water-Electrolyte Imbalance
PubMed: 33873189
DOI: 10.1159/000515604 -
CEN Case Reports Nov 2021Moyamoya disease (MMD) has long been known to be associated with hypertension. While renal artery stenosis (RAS) is considered one of the causes of hypertension with...
Moyamoya disease (MMD) has long been known to be associated with hypertension. While renal artery stenosis (RAS) is considered one of the causes of hypertension with MMD, most hypertension causes remain unexplained. A boy with MMD was diagnosed with renovascular hypertension (RVH) due to left-sided RAS by angiography. Although nephrectomy on the affected side for unilateral RVH was performed, hypertension poorly improved. Histopathological examination of the resected specimens revealed that the vascular lumen not only of the renal artery but also of peripheral vessels in the renal parenchyma was narrowed. He developed end-stage renal disease caused by multiple wasp stings and received a kidney transplant from a living donor with his remaining right kidney resected. His hypertension improved dramatically just after the operation. In histopathological findings, the narrowed vascular lumen was also observed in the resected right renal parenchyma similar to that in the left kidney. In our case, these pathological findings were the same as those of major vessels previously reported in MMD patients. Immunohistochemical staining with anti-renin antibody on bilateral intrinsic kidneys was strongly revealed in the Juxtaglomerular apparatus. He has been normotensive with the minimum amount of amlodipine since transplantation and resection of his intrinsic right kidney. This is the first report to show the possibility that peripheral arterial stenosis in the renal parenchyma due to MMD would result in refractory hypertension. If MMD patients have hypertension of unknown origin without significant RAS, it should be considered that the etiology may be peripheral arterial stenosis in the renal parenchyma.
Topics: Angiography; Humans; Hypertension, Renovascular; Infant; Kidney; Male; Moyamoya Disease; Renal Artery; Renal Artery Obstruction
PubMed: 33826107
DOI: 10.1007/s13730-021-00594-x