The pathomorphology of the renal cortex depending of arterial hypertension duration course

The kidneys autopsy material of persons with arterial hypertension in different duration was examined. Morphometry of the renal corpuscle area and cortical and juxtamedullary nephrons vascular glomeruli was performed. There were 4 groups - a control group (with a normal blood pressure level), and groups with arterial hypertension - the initial stage (group 2), arterial hypertension for 5-10 years (group 3), long-term arterial hypertension - more than 10 years (group 4). It was found that cortical nephrons are distinguished by earlier and more pronounced hyperplasia of the vascular glomerulus, they are more rapidly exposed to sclerosis, which appears in the 5-10th year of the course of the disease. The hyperplasia of the vascular glomerulus components is progressively increasing in juxtaglomerular nephrons, they are less susceptible to sclerosis processes. Key words: arterial hypertension, juxtaglomerular apparatus, juxtamedullary nephrons, vascular glomerulus.

Mineralocorticoid receptor signaling is implicated in carfilzomib-induced increase in blood pressure

Introduction Carfilzomib (Cfz), an irreversible proteasome inhibitor, is a first line antineoplastic agent indicated for relapsed/refractory multiple myeloma, with its clinical use being hampered by cardiovascular adverse effects. Hypertension, is the most common cardiovascular side effect of Cfz, remaining of unknown pathogenicity. Purpose Considering that management of Cfz-related hypertension remains an unmet clinical need and that renal function plays a pivotal role in blood pressure regulation we sought to investigate the renal contribution in Cfz-induced hypertension. Methods We have previously established a translational model of Cfz-induced cardiomyopathy, based on clinically applicable dose regimens and we have concluded that two and four dose protocols successfully resemble the clinical observations in vivo. Herein, sixty C57Bl/6 male mice (12–14 weeks old) were randomized to: 1. Two doses Protocol: i. Control (N/S 0.9%), ii. Cfz (8mg/kg) for two consecutive days; and 2. Four doses Protocol: i. Control (N/S 0.9%), ii. Cfz (8mg/kg) for seven days intraperitoneally. Systolic (SBP) and diastolic blood pressure (DBP) were measured by tail cuffs; the latter protocol was repeated and urine collection was performed via metabolic cages studies. Renal samples were collected for histological, proteomic, metabolomic and molecular signaling analyses. Finally, eplerenone, a mineralocorticoid receptor (MR) blocker, was orally co-administered with Cfz to the mice daily (165 mg/kg) in the four doses protocol. Results Cfz increased SBP only in the four doses protocol (78.50±2.05 vs 68.20±0.73 in the Control group, **P<0.01). Histological evaluation of the kidneys revealed a juxtaglomerular apparatus hyperplasia (JAH) in the same dose regimen. Proteomic analysis presented that metabolic and transport of small molecules pathways were differentially regulated in the Cfz treated murine kidneys. Metabolomic analysis revealed an increase in urea cycle metabolites (L-Alanine, L-Glutamine, glutamate, aspartate) and taurine content in the kidneys. Additionally, mice presented decreased diuresis without any differences in other metabolic parameters. In parallel an upregulation of β-ENaC expression and activation of MR/SGK-1 signaling in the kidneys was observed, indicating that Cfz activates MR signaling. Co-administration of eplerenone and Cfz, restored diuresis, decreased SBP and inhibited MR/SGK-1 signaling in the kidneys. Conclusions Activation of MR signaling by Cfz in the kidneys orchestrates renal water/salt retention and drives an increase in blood pressure in vivo. Histological and metabolomic analyses present that Cfz induces an acute kidney injury and a tonicity increase. Eplerenone reversed Cfz-induced blood pressure increase and restored diuresis by inhibiting MR/SGK-1 signaling. Therefore, MR blockade emerges as a potent therapeutic approach against Cfz-related cardiovascular adverse events. FUNDunding Acknowledgement Type of funding sources: None.

Overview of Scleroderma Renal Crisis - A Review

Scleroderma renal crisis is a life-threatening condition. It usually starts with a sudden onset of severe hypertension, followed by renal failure, hypertensive encephalopathy, congestive heart failure, and/or microangiopathic hemolytic anemia. Renal ischemia, hyperplasia of the juxtaglomerular apparatus, activation of the renin-angiotensin-aldosterone system (RAAS), and an increase in blood pressure are caused by decreased blood flow caused by structural changes in the blood vessels as well as renal vasospasm ("Raynaud's phenomenon"). This overview discusses the evaluation, diagnosis, and treatment of scleroderma renal crisis, emphasizing the importance of early detection of disease, strong correlation of corticosteroids intake and the disease incidence, and best approach of such cases.

Merokok dan Gangguan Fungsi Ginjal

Smoking increases the production of angiotensin II as an effect of renin secretion stimulated by the efferent sympathetic system through beta-1 adrenergic stimulation of the juxtaglomerular apparatus. Angiotensin II will cause tubular and glomerular injuries through the mechanism of pressure-induced renal injury and ischemia-induced renal injury as a secondary result of intrarenal vasoconstriction and decreased renal blood flow. In addition, there is secondary tubular injury due to angiotensin-induced proteinuria. Angiotensin II activates renal fibroblasts to undergo differentiation into myofibroblasts, stimulates TGF-ß profibrotic cytokines, induces oxidative stress, stimulates chemokines and osteopontin which can cause local inflammation, and stimulates mesangial cell proliferation and hypertrophy. Glomerular capillary hypertension causes an increase in glomerular permeability resulting in an increase in albumin filtration which will further trigger kidney damage through various pathways, including induction of tubular chemokine expression and activation of complement leading to infiltration of inflammatory cells in the interstitium and trigger fibrogenesis. This phenomenon involves endothelial cells and glomerular podocytes and will trigger exacerbation of proteinuria and glomerulosclerosis with the end result in the formation of kidney scar tissue and a decrease in glomerular filtration rate (GFR).Keywords: smoking; renal function; TGF-ß; glomerular filtration rate (GFR) Abstrak: Merokok akan meningkatkan produksi angiotensin II sebagai efek dari sekresi renin yang distimulasi oleh sistim simpatik eferen melalui stimulasi beta-1 adrenergik pada aparatus jukstaglomerular. Angiotensin II akan menyebabkan cedera tubulus dan glomerulus melalui mekanisme pressure-induced renal injury dan ischemia-induced renal injury sebagai akibat sekunder dari vasokonstriksi intrarenal dan penurunan aliran darah ginjal. Selain itu terjadi cedera tubulus sekunder dari proteinuria yang diinduksi angiotensin. Angiotensin II akan mengaktifkan fibroblas ginjal berdiferensiasi menjadi miofibroblas, menstimulasi sitokin profibrotik TGF-ß, menginduksi stres oksidatif, menstimulasi kemokin dan osteopontin yang dapat menyebabkan inflamasi local, dan menstimulasi proliferasi dan hipertrofi sel mesangial. Hipertensi kapiler glomerulus akan menyebabkan peningkatan permeabilitas glomerulus sehingga terjadi peningkatan filtrasi albumin yang selanjutnya memicu kerusakan ginjal melalui berbagai jalur, diantaranya induksi ekspresi kemokin tubulus dan aktivasi komplemen yang akan mengarah pada infiltrasi sel-sel inflamasi pada interstisium dan memicu fibrogenesis. Fenomena ini melibatkan sel endotel dan podosit glomerulus dan akan mencetuskan eksaserbasi proteinuria dan glomerulosklerosis dengan hasil akhir berupa terbentuknya jaringan parut ginjal dan penurunan laju filtrasi glomerulus (LFG).Kata kunci: merokok; fungsi ginjal; TGF-ß; laju filtrasi glomerulus (LFG)

The Role of Serum Chloride in Acute and Chronic Heart Failure: A Narrative 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.

Connexin Signaling in the Juxtaglomerular Apparatus (JGA) of Developing, Postnatal Healthy and Nephrotic Human Kidneys

Our study analyzed the expression pattern of different connexins (Cxs) and renin positive cells in the juxtaglomerular apparatus (JGA) of developing, postnatal healthy human kidneys and in nephrotic syndrome of the Finnish type (CNF), by using double immunofluorescence, electron microscopy and statistical measuring. The JGA contained several cell types connected by Cxs, and consisting of macula densa, extraglomerular mesangium (EM) and juxtaglomerular cells (JC), which release renin involved in renin-angiotensin- aldosteron system (RAS) of arterial blood pressure control. During JGA development, strong Cx40 expression gradually decreased, while expression of Cx37, Cx43 and Cx45 increased, postnatally showing more equalized expression patterning. In parallel, initially dispersed renin cells localized to JGA, and greatly increased expression in postnatal kidneys. In CNF kidneys, increased levels of Cx43, Cx37 and Cx45 co-localized with accumulations of renin cells in JGA. Additionally, they reappeared in extraglomerular mesangial cells, indicating association between return to embryonic Cxs patterning and pathologically changed kidney tissue. Based on the described Cxs and renin expression patterning, we suggest involvement of Cx40 primarily in the formation of JGA in developing kidneys, while Cx37, Cx43 and Cx45 might participate in JGA signal transfer important for postnatal maintenance of kidney function and blood pressure control.