scholarly journals Molecular Mechanisms of Kidney Injury and Repair in Arterial Hypertension

2019 ◽  
Vol 20 (9) ◽  
pp. 2138 ◽  
Author(s):  
Laura Katharina Sievers ◽  
Kai-Uwe Eckardt
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Arterial Hypertension ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Kidney Injury ◽  
Cell Types ◽  
Molecular Signaling ◽  
Systemic Signaling ◽  
Injury And Repair

The global burden of chronic kidney disease is rising. The etiologies, heterogeneous, and arterial hypertension, are key factors contributing to the development and progression of chronic kidney disease. Arterial hypertension is induced and maintained by a complex network of systemic signaling pathways, such as the hormonal axis of the renin-angiotensin-aldosterone system, hemodynamic alterations affecting blood flow, oxygen supply, and the immune system. This review summarizes the clinical and histopathological features of hypertensive kidney injury and focusses on the interplay of distinct systemic signaling pathways, which drive hypertensive kidney injury in distinct cell types of the kidney. There are several parallels between hypertension-induced molecular signaling cascades in the renal epithelial, endothelial, interstitial, and immune cells. Angiotensin II signaling via the AT1R, hypoxia induced HIFα activation and mechanotransduction are closely interacting and further triggering the adaptions of metabolism, cytoskeletal rearrangement, and profibrotic TGF signaling. The interplay of these, and other cellular pathways, is crucial to balancing the injury and repair of the kidneys and determines the progression of hypertensive kidney disease.

scholarly journals Multi-Target Drugs for Kidney Diseases

Kidney360 ◽  
2021 ◽  
pp. 10.34067/KID.0003582021
Author(s):  
John D. Imig ◽  
Daniel Merk ◽  
Eugen Proschak
Keyword(s):  
Kidney Disease ◽  
Signaling Pathways ◽  
Transforming Growth Factor ◽  
Metabolic Diseases ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Glomerular Nephritis ◽  
Cell Signaling Pathways

Kidney diseases such as acute kidney injury (AKI), chronic kidney disease (CKD), and glomerular nephritis can lead to dialysis and the need for kidney transplantation. The pathologies for kidney diseases are extremely complex, progress at different rates, and involve several cell types and cell-signaling pathways. Complex kidney diseases require therapeutics that can act on multiple targets. In the past ten years, in silico design of drugs has allowed for multi-target drugs to go quickly from concept to reality. Several multi-target drugs have been successfully made that target arachidonic acid pathways and transcription factors to treat inflammatory, fibrotic, and metabolic diseases. Multi-target drugs have also demonstrated great potential to treat diabetic nephropathy and fibrotic kidney disease. These drugs act by decreasing renal transforming growth factor-β (TGF-β) signaling, inflammation, mitochondrial dysfunction, and oxidative stress. There are several other recently developed multi-target drugs that have yet to be tested for their ability to combat kidney diseases. Overall, there is excellent potential for multi-target drugs that act on several cell types and signaling pathways to treat kidney diseases.

scholarly journals Huaier Extract Attenuates Acute Kidney Injury to Chronic Kidney Disease Transition by Inhibiting Endoplasmic Reticulum Stress and Apoptosis via miR-1271 Upregulation

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Jing-Ying Zhao ◽  
Yu-Bin Wu
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Endoplasmic Reticulum ◽  
Kidney Disease ◽  
Endoplasmic Reticulum Stress ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury

Endoplasmic reticulum stress (ERS) is strongly associated with acute kidney injury (AKI) to chronic kidney disease (CKD) transition. Huaier extract (HE) protects against kidney injury; albeit, the underlying mechanism is unknown. We hypothesized that HE reduces kidney injury by inhibiting ERS. In this study, using an AKI-CKD mouse model of ischemia-reperfusion injury (IRI), we evaluated the effect of HE on AKI-CKD transition. We also explored the underlying molecular mechanisms in this animal model and in the HK-2 human kidney cell line. The results showed that HE treatment improved the renal function, demonstrated by a significant decrease in serum creatinine levels after IRI. HE appreciably reduced the degree of kidney injury and fibrosis and restored the expression of the microRNA miR-1271 after IRI. Furthermore, HE reduced the expression of ERS markers glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) and inhibited apoptosis in the IRI group. This in vivo effect was supported by in vitro results in which HE inhibited apoptosis and decreased the expression of CHOP and GRP78 induced by ERS. We demonstrated that CHOP is a target of miR-1271. In conclusion, HE reduces kidney injury, probably by inhibiting apoptosis and decreasing the expression of GRP78 and CHOP via miR-1271 upregulation.

scholarly journals Vascular Calcification in Chronic Kidney Disease: Diversity in the Vessel Wall

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 404
Author(s):  
Prabhatchandra Dube ◽  
Armelle DeRiso ◽  
Mitra Patel ◽  
Dhanushya Battepati ◽  
Bella Khatib-Shahidi ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Vascular Calcification ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Complex Process ◽  
Cardiovascular Morbidity And Mortality ◽  
Depth Analysis ◽  
Multiple Cell ◽  
Different Cell Types

Vascular calcification (VC) is one of the major causes of cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). VC is a complex process expressing similarity to bone metabolism in onset and progression. VC in CKD is promoted by various factors not limited to hyperphosphatemia, Ca/Pi imbalance, uremic toxins, chronic inflammation, oxidative stress, and activation of multiple signaling pathways in different cell types, including vascular smooth muscle cells (VSMCs), macrophages, and endothelial cells. In the current review, we provide an in-depth analysis of the various kinds of VC, the clinical significance and available therapies, significant contributions from multiple cell types, and the associated cellular and molecular mechanisms for the VC process in the setting of CKD. Thus, we seek to highlight the key factors and cell types driving the pathology of VC in CKD in order to assist in the identification of preventative, diagnostic, and therapeutic strategies for patients burdened with this disease.

SGLT2 inhibition for cardiovascular diseases, chronic kidney disease and NAFLD

Endocrinology ◽  
2021 ◽  
Author(s):  
Moein Ala
Keyword(s):  
Chronic Kidney Disease ◽  
Clinical Trials ◽  
Cardiovascular Diseases ◽  
Kidney Disease ◽  
Signaling Pathways ◽  
Observational Studies ◽  
Animal Studies ◽  
Molecular Mechanisms ◽  
Renal Diseases ◽  
Beneficial Effects

Abstract Sodium glucose cotransporter 2 (SGLT-2) inhibitors are the latest class of anti-diabetic medications. They prevent glucose reabsorption in the proximal convoluted tubule to decrease blood sugar. Several animal studies revealed that SGLT-2 is profoundly involved in the inflammatory response, fibrogenesis and regulation of numerous intracellular signaling pathways. Likewise, SGLT-2 inhibitors markedly attenuated inflammation and fibrogenesis and improved the function of damaged organ in animal studies, observational studies and clinical trials. SGLT-2 inhibitors can decrease blood pressure and ameliorate hypertriglyceridemia and obesity. Likewise, they improve the outcome of cardiovascular diseases such as heart failure, arrhythmias and ischemic heart disease. SGLT-2 inhibitors are associated with lower cardiovascular and all-cause mortality, as well. Meanwhile, they protect against non-alcoholic fatty liver disease (NAFLD), chronic kidney disease (CKD), acute kidney injury (AKI), and improve micro- and macroalbuminuria. SGLT-2 inhibitors can reprogram numerous signaling pathways to improve NAFLD, cardiovascular diseases and renal diseases. For instance, they enhance lipolysis, ketogenesis, mitochondrial biogenesis and autophagy while they attenuate renin-angiotensin-aldosterone system (RAAS), lipogenesis, endoplasmic reticulum (ER) stress, oxidative stress, apoptosis and fibrogenesis. This review explains the beneficial effects of SGLT-2 inhibitors on NAFLD, cardiovascular and renal diseases and dissects the underlying molecular mechanisms in detail. This narrative review explains the beneficial effects of SGLT-2 inhibitors on NAFLD, cardiovascular and renal diseases using the results of latest observational studies, clinical trials and meta-analyses. Thereafter, it dissects the underlying molecular mechanisms involved in the clinical effects of SGLT-2 inhibitors on these diseases.

scholarly journals Kidney Single-Cell Atlas Reveals Myeloid Heterogeneity in Progression and Regression of Kidney Disease

2020 ◽  
Vol 31 (12) ◽  
pp. 2833-2854
Author(s):  
Bryan R. Conway ◽  
Eoin D. O’Sullivan ◽  
Carolynn Cairns ◽  
James O’Sullivan ◽  
Daniel J. Simpson ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Kidney Disease ◽  
Single Cell ◽  
Single Cells ◽  
Kidney Injury ◽  
Myeloid Cell ◽  
Cell Types ◽  
Blood Exchange ◽  
Transcriptomic Level ◽  
Injury And Repair

BackgroundLittle is known about the roles of myeloid cell subsets in kidney injury and in the limited ability of the organ to repair itself. Characterizing these cells based only on surface markers using flow cytometry might not provide a full phenotypic picture. Defining these cells at the single-cell, transcriptomic level could reveal myeloid heterogeneity in the progression and regression of kidney disease.MethodsIntegrated droplet– and plate-based single-cell RNA sequencing were used in the murine, reversible, unilateral ureteric obstruction model to dissect the transcriptomic landscape at the single-cell level during renal injury and the resolution of fibrosis. Paired blood exchange tracked the fate of monocytes recruited to the injured kidney.ResultsA single-cell atlas of the kidney generated using transcriptomics revealed marked changes in the proportion and gene expression of renal cell types during injury and repair. Conventional flow cytometry markers would not have identified the 12 myeloid cell subsets. Monocytes recruited to the kidney early after injury rapidly adopt a proinflammatory, profibrotic phenotype that expresses Arg1, before transitioning to become Ccr2+ macrophages that accumulate in late injury. Conversely, a novel Mmp12+ macrophage subset acts during repair.ConclusionsComplementary technologies identified novel myeloid subtypes, based on transcriptomics in single cells, that represent therapeutic targets to inhibit progression or promote regression of kidney disease.

scholarly journals Molecular Mechanisms of the Acute Kidney Injury to Chronic Kidney Disease Transition: An Updated View

2019 ◽  
Vol 20 (19) ◽  
pp. 4941 ◽  
Author(s):  
Francesco Guzzi ◽  
Luigi Cirillo ◽  
Rosa Maria Roperto ◽  
Paola Romagnani ◽  
Elena Lazzeri
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Molecular Mechanisms ◽  
Kidney Injury ◽  
Small Population ◽  
Acute Injury ◽  
Tubular Necrosis ◽  
Kidney Disease Progression ◽  
Renal Progenitors

Increasing evidence has demonstrated the bidirectional link between acute kidney injury (AKI) and chronic kidney disease (CKD) such that, in the clinical setting, the new concept of a unified syndrome has been proposed. The pathophysiological reasons, along with the cellular and molecular mechanisms, behind the ability of a single, acute, apparently self-limiting event to drive chronic kidney disease progression are yet to be explained. This acute injury could promote progression to chronic disease through different pathways involving the endothelium, the inflammatory response and the development of fibrosis. The interplay among endothelial cells, macrophages and other immune cells, pericytes and fibroblasts often converge in the tubular epithelial cells that play a central role. Recent evidence has strengthened this concept by demonstrating that injured tubules respond to acute tubular necrosis through two main mechanisms: The polyploidization of tubular cells and the proliferation of a small population of self-renewing renal progenitors. This alternative pathophysiological interpretation could better characterize functional recovery after AKI.

Hypertension in Chronic Kidney Disease: Novel Insights

2020 ◽  
Vol 16 (1) ◽  
pp. 45-54 ◽  
Author(s):  
Anila Duni ◽  
Evangelia Dounousi ◽  
Paraskevi Pavlakou ◽  
Theodoros Eleftheriadis ◽  
Vassilios Liakopoulos
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Arterial Hypertension ◽  
Treatment Strategies ◽  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Renal Protection ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Meta Analyses

Management of arterial hypertension in patients with chronic kidney disease (CKD) remains a major challenge due to its high prevalence and associations with cardiovascular disease (CVD) and CKD progression. Several clinical trials and meta-analyses have demonstrated that aggressive treatment of hypertension in patients with and without CKD lowers the risk of CVD and all-cause mortality, nevertheless the effects of blood pressure (BP) lowering in terms of renal protection or harm remain controversial. Both home and ambulatory BP estimation have shown that patients with CKD display abnormal BP patterns outside of the office and further investigation is required, so as to compare the association of ambulatory versus office BP measurements with hard outcomes and adjust treatment strategies accordingly. Although renin-angiotensin system blockade appears to be beneficial in patients with advanced CKD, especially in the setting of proteinuria, discontinuation of renin-angiotensin system inhibition should be considered in the setting of frequent episodes of acute kidney injury or hypotension while awaiting the results of ongoing trials. In light of the new evidence in favor of renal denervation in arterial hypertension, the indications and benefits of its application in individuals with CKD need to be clarified by future studies. Moreover, the clinical utility of the novel players in the pathophysiology of arterial hypertension and CKD, such as microRNAs and the gut microbiota, either as markers of disease or as therapeutic targets, remains a subject of intensive research.

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