Macula densa

The glomerular vascular pole is the gate for the afferent and efferent arterioles and mesangial cells and a frequent location of peripolar cells with an unclear function. It has been studied in definitive detail for >30 years, and functionally interrogated in the context of signal transduction from the macula densa to the mesangial cells and afferent arteriolar smooth muscle cells from 10 to 20 years ago. Two recent discoveries shed additional light on the vascular pole, with possibly far-reaching implications...

Increased NaCl at the macula densa, the same stimulus of the tubuloglomerular feedback (TGF), also induces intracellular alkalinization (pH: from 7.4 to 7.8) and enhances nitric oxide (NO) generation. Neuronal NO synthase (NOS1) is the primary isoform of NOS expressed in the macula densa and its activity is strongly pH-dependent. Nevertheless, the impact of pH on the catalytic capacity of NOS1 remains controversial with inconsistent observations. A potential explanation for this discrepancy may be due to the presence of different splice variants of NOS1 (NOS1α and NOS1β)...

The renal response to hyperkalemia is mediated by increased K secretion within connecting tubule (CNT), flux that is modulated by tubular effects (e.g. aldosterone) in conjunction with increased luminal flow. It is established that peritubular K blunts Na reabsorption in proximal tubule, thick ascending Henle limb, and distal convoluted tubule (DCT). While any such reduction may augment CNT delivery, the relative contribution of each is uncertain. The kidney model of this lab was recently advanced with representation of cortical labyrinth and medullary ray...

The regulation of renin release from juxtaglomerular (JG) cells at the systemic or local level has been extensively investigated and well understood. It includes three primary mechanisms: intrarenal baroreceptor, salt feedback via macula densa, and β1-adrenergic receptor activation. However, further understanding of the control of renin synthesis and secretion in JG cells at the cellular or molecular level is limited. Additionally, JG cells are generally considered to be derived from the smooth muscle (SM) cells in the afferent arterioles via a reversible metaplastic transformation...

Although it is not certain whether some characteristics of the mammalian fetus/embryo may repeat the adult stage of ancestral vertebrates, comparison of these two time-dependent processes should provide new insight into the molecular and functional evolution and its significance. Here we discuss two important biological models: 1) Renin-angiotensin system (RAS) and 2) Urine concentration mechanism. Renin is a hormone and substrate-dependent enzyme secreted mostly by the juxtaglomerular (JG) cells of the afferent arteriole located at the vascular pole of the glomerulus...

Circulating and kidney resident immune cells preferentially home in and around the glomerulus compared to other vascular beds in both normal and inflammatory states, suggesting the presence of unique antimicrobial mechanisms in the glomerular microcirculation that protect the kidney filter. However, the underlying cell and molecular mechanisms are largely unknown. Macula densa (MD) cells are localized at the glomerular vascular entrance as a unique juxtaglomerular cell type and are known to control glomerular hemodynamics, and more recently, glomerular tissue remodeling...

Ferritin is the main intracellular storage of iron. Animal studies show that female liver and kidney express more ferritin and accumulate more iron than male. However, no study so far has investigated sex and age differences in light (FtL) and heavy (FtH) ferritin chain expression. To address this, we relied on specific antibodies and immunochemical methods to analyse the expression of both ferritin chains in the liver and kidney of 3-month and 2-year-old male and female Wistar rats. To see how sex hormones may affect expression we also studied adult animals gonadectomised at the age of 10 weeks...

The kidney is a complex organ that consists of various types of cells. It is occasionally difficult to resolve molecular alterations and possible perturbations that the kidney experiences due to drug-induced damage. In this study, we performed spatial and single-cell transcriptome analysis of rat kidneys and constructed a precise rat renal cell atlas with spatial information. Using the constructed catalog, we were able to characterize cells of several minor populations, such as macula densa or juxtaglomerular cells...

Cyclooxygenase (Cox) inhibitors are known to have severe side effects during renal development. These consist of reduced renal function, underdeveloped subcapsular glomeruli, interstitial fibrosis, and thinner cortical tissue. Global genetic deletion of Cox-2 mimics the phenotype observed after application of Cox inhibitors. This study aimed to investigate which cell types express Cox-2 and prostaglandin E2 receptors and what functions are mediated through this pathway during renal development. Expression of EP2 and EP4 mRNA was detected by RNAscope mainly in descendants of FoxD1+ stromal progenitors; EP1 and EP3, on the other hand, were expressed in tubules...

The renal response to acute hyperkalemia is mediated by increased K secretion within connecting tubule (CNT), flux that is modulated by tubular effects (e.g. aldosterone) in conjunction with increased luminal flow. There is ample evidence that peritubular K blunts Na reabsorption in proximal tubule, thick ascending Henle limb, and distal convoluted tubule (DCT). While any such reduction may augment CNT delivery, the relative contribution of each is uncertain. The kidney model of this lab was recently advanced with representation of cortical labyrinth and medullary ray...

OBJECTIVE: Induction of hypertension by diabetic nephropathy (DN) may be dependent on increased renin secretion from juxtaglomerular cells (JGC). To reveal that the mechanisms of cell adhesion and cell motility associated with β1-integrin phosphorylation contribute to pressure sensing in JGC, we tested the β1-integrin phosphorylation levels in renal tissue and the relationship between β1-integrin phosphorylation and the expression of renin. METHODS: The DN rat model was generated by intravenous injection of streptozotocin (STZ, 60 mg/kg body weight)...

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...

The kidneys play an important role in blood pressure regulation under normal and pathological conditions. We examined the histological changes and expression patterns of cyclooxygenase-2, renin, and (pro)renin receptor (PRR) in the renal cortex of prehypertensive spontaneously hypertensive rats (SHRs) and Wistar Kyoto rats (WKYs). Moreover, blood pressure and plasma urea, creatinine, angiotensin II, and angiotensin (1-7) levels were measured. The results showed that both strains had similar blood pressure and plasma urea and creatinine levels...

Sodium-glucose co-transporter 2 inhibitors (SGLT2-Is) have emerged as a promising class of antidiabetic drugs with cardioprotective and renoprotective effects in patients with type 2 diabetes (T2D). The sodium-glucose co-transporters 1 and 2 (SGLT 1 and SGLT2) located in the renal proximal tubules are responsible for glucose reabsorption from the glomerular filtrate back into the systemic circulation. Inhibition of SGLT2, which accounts for about 90% of the glucose reabsorption, leads to a significant reduction in blood glucose levels and a concomitant increase in the urinary excretion of glucose (glycosuria)...

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...

Hypertension is a common comorbid condition in patients with diabetes. The pathogenesis of hypertension in diabetes has not been fully clarified. Primary tubular hyperreabsorption may contribute, which may be counteracted by glomerular hyperfiltration in the early diabetic kidney. In this study, we hypothesize that in early diabetes, the macula densa neuronal nitric oxide synthase (NOS1)-derived nitric oxide (NO) production is enhanced, which blunts tubuloglomerular feedback (TGF) response, promotes glomerular hyperfiltration, and maintains normal blood pressure; conversely, insufficient NO generation by the macula densa induces hypertension by lowering glomerular filtration rate and thus inhibiting natriuresis...

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...

At the onset of diabetes, the kidney grows large and the glomerular filtration rate becomes abnormally high. These structural and hemodynamics changes affect kidney function and may contribute to the development of chronic kidney disease. The goal of this study is to analyze how kidney function is altered in patients with diabetes and the renal effects of an anti-hyperglyceamic therapy that inhibits the sodium-glucose cotransporter 2 (SGLT2) in the proximal convoluted tubules. To accomplish that goal, we have developed a computational model of kidney function in a patient with diabetes and conducted simulations to study the effects of diabetes and SGLT2 inhibition on solute and water transport along the nephrons...

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...

Molecular characterization of the individual cell types in human kidney as well as model organisms are critical in defining organ function and understanding translational aspects of biomedical research. Previous studies have uncovered gene expression profiles of several kidney glomerular cell types, however, important cells, including mesangial (MCs) and glomerular parietal epithelial cells (PECs), are missing or incompletely described, and a systematic comparison between mouse and human kidney is lacking. To this end, we use Smart-seq2 to profile 4332 individual glomerulus-associated cells isolated from human living donor renal biopsies and mouse kidney...