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Selected factors that may cause hypertension in chronic kidney disease * .

Selected factors that may cause hypertension in chronic kidney disease * .

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Hypertension is both an important cause and consequence of chronic kidney disease. Evidence from numerous clinical trials has demonstrated the benefit of blood pressure control. However, it remains unclear whether available results could be extrapolated to patients with chronic kidney diseases because most studies on hypertension have excluded pati...

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... has been replicated in hypertensive uremic humans [31]. Table 1 shows a list of factors proposed to cause hypertension in CKD along with their corresponding mechanisms. Activation of the renin-angiotensin system (RAS) has been well documented in dialysis patients with uncon- trolled hypertension despite optimized ultrafiltration [32]. ...

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... Hypertension (HTN) is one of the most important risk factors for some NCD such as cardiovascular diseases, stroke, and chronic kidney disease. It is estimated to cause 12.8% of all-cause mortality and 57 million disability adjusted life years (DALY) [3][4][5][6][7]. Yet, many individuals are often unaware of having HTN, especially at its initial phases, due to a lack of specific clinical signs and do not seek treatment and control of HTN; therefore, its detection in the community is usually delayed [8]. ...
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Background Elevated blood pressure is associated with cardiovascular disease, stroke and chronic kidney disease. In this study, we examined the socioeconomic inequality and its related factors in prevalence, Awareness, Treatment and Control (ATC) of hypertension (HTN) in Iran. Method The study used data from the recruitment phase of The Prospective Epidemiological Research Studies in IrAN (PERSIAN). A sample of 162,842 adults aged > = 35 years was analyzed. HTN was defined according to the Joint National Committee)JNC-7(. socioeconomic inequality was measured using concentration index (Cn) and curve. Results The mean age of participants was 49.38(SD = ± 9.14) years and 44.74% of the them were men. The prevalence of HTN in the total population was 22.3%(95% CI: 20.6%; 24.1%), and 18.8%(95% CI: 16.8%; 20.9%) and 25.2%(95% CI: 24.2%; 27.7%) in men and women, respectively. The percentage of awareness treatment and control among individuals with HTN were 77.5%(95% CI: 73.3%; 81.8%), 82.2%(95% CI: 70.2%; 81.6%) and 75.9%(95% CI: 70.2%; 81.6%), respectively. The Cn for prevalence of HTN was -0.084. Two factors, age (58.46%) and wealth (32.40%), contributed most to the socioeconomic inequality in the prevalence of HTN. Conclusion The prevalence of HTN was higher among low-SES individuals, who also showed higher levels of awareness. However, treatment and control of HTN were more concentrated among those who had higher levels of SES, indicating that people at a higher risk of adverse event related to HTN (the low SES individuals) are not benefiting from the advantage of treatment and control of HTN. Such a gap between diagnosis (prevalence) and control (treatment and control) of HTN needs to be addressed by public health policymakers.
... This result is consistent withprevious studies that reportedthat the incidence of "HTN is higher among patients with CKD, progressively increasing with the severity of CKD". [13] CMD is a marker for assessing the presence of nephropathy. Our findings also consisted with Gareeballah et al. who found that CMD was mainly disturbed in acute parenchymal disease and lost in chronic end-stage parenchymal illness. ...
... [14] A strong association was reported between HTN and diabetic nephropathy. [13] Furthermore, the incidence of HTN varies with the etiology of CKD. Therefore, lack of CMD is attributed to increased cortical echogenicity. ...
... Arterial hypertension (AH) intensifies proteinuria and therefore accelerates CKD aggravation [10,11,12]. The risk of cardiovascular complications and advance of kidney lesions increases in proportion to increased proteinuria [13,14,16]. Hypotensive therapy with diabetic nephropathy is indicated not only to reduce AH but to decrease the risk of cardiovascular diseases and slow down advance of kidney lesions [15,17,18]. ...
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Diabetes mellitus considerably accelerates advance of chronic kidney disease (CKD) reducing glomerular filtration rate (GFR) by 12-15 ml/min per year resulting in much earlier deterioration of the renal function-at a younger age. One more important mechanism of CKD aggravation is associated with proteinuria. Continuous increase of protein content in the u rine is an important symptom of kidney lesion. Albumin excretion is an important marker of diabetes mellitus. In case of CKD caused by diabetic nephropathy proteinuria is not only a sign of the disease but its important pathogenic mechanism of advancing. Arterial hypertension (AH) intensifies proteinuria and therefore accelerates CKD aggravation. Antihypertensive therapy with diabetic nephropathy is indicated not only to reduce AH but to decrease the risk of cardiovascular diseases and slow down kidney lesions. Choosing antihypertensive agents special attention should be paid to angiotensin converting enzyme (ACE) inhibitors and calcium channel-blocking agents with their typical nephroprotection, which slows down advance of chronic kidney disease.
... e capability of the reninangiotensin system (RAS) enzymes or receptor antagonists for the treatment of hypertension reveals the important role of RAS. Physiologically, RAS plays a key role in regulating blood pressure (BP) and electrolytes homeostasis while its activation contributes to the pathogenesis of hypertension [4][5][6]. RAS-dependent hypertension leads to kidney fibrosis and progressive CKD [4,5], while the latter is the most common cause of secondary hypertension, and it is an independent risk factor for cardiovascular outcomes [5,7]. e most important RAS component is angiotensin II (Ang II) which acts mostly via two major receptors of type 1 (AT 1 R) and type 2 (AT 2 R) [8]. ...
... Physiologically, RAS plays a key role in regulating blood pressure (BP) and electrolytes homeostasis while its activation contributes to the pathogenesis of hypertension [4][5][6]. RAS-dependent hypertension leads to kidney fibrosis and progressive CKD [4,5], while the latter is the most common cause of secondary hypertension, and it is an independent risk factor for cardiovascular outcomes [5,7]. e most important RAS component is angiotensin II (Ang II) which acts mostly via two major receptors of type 1 (AT 1 R) and type 2 (AT 2 R) [8]. ...
... Physiologically, RAS plays a key role in regulating blood pressure (BP) and electrolytes homeostasis while its activation contributes to the pathogenesis of hypertension [4][5][6]. RAS-dependent hypertension leads to kidney fibrosis and progressive CKD [4,5], while the latter is the most common cause of secondary hypertension, and it is an independent risk factor for cardiovascular outcomes [5,7]. e most important RAS component is angiotensin II (Ang II) which acts mostly via two major receptors of type 1 (AT 1 R) and type 2 (AT 2 R) [8]. ...
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Long-term hypertension is known as a major risk factor for cardiovascular and chronic kidney disease (CKD). The Renin-angiotensin system (RAS) plays a key role in hypertension pathogenesis. Angiotensin II (Ang II) enhancement in Ang II-dependent hypertension leads to progressive CKD and kidney fibrosis. In the two-kidney one-clip model (2K1C), more renin is synthesized in the principal cells of the collecting duct than juxtaglomerular cells (JGCs). An increase of renal Ang I and Ang II levels and a decrease of renal cortical and medullary Ang 1–7 occur in both kidneys of the 2K1C hypertensive rat model. In addition, the activity of the angiotensin-converting enzyme (ACE) increases, while ACE2’s activity decreases in the medullary region of both kidneys in the 2K1C hypertensive model. Also, the renal prolyl carboxypeptidase (PrCP) expression and its activity reduce in the clipped kidneys. The imbalance in the production of renal ACE, ACE2, and PrCP expression causes the progression of renal injury. Intrarenal angiotensinogen (AGT) expression and urine AGT (uAGT) excretion rates in the unclipped kidney are greater than the clipped kidney in the 2K1C hypertensive rat model. The enhancement of Ang II in the clipped kidney is related to renin secretion, while the elevation of intrarenal Ang II in the unclipped kidney is related to stimulation of AGT mRNA and protein in proximal tubule cells by a direct effect of systemic Ang II level. Ang II-dependent hypertension enhances macrophages and T-cell infiltration into the kidney which increases cytokines, and AGT synthesis in proximal tubules is stimulated via cytokines. Accumulation of inflammatory cells in the kidney aggravates hypertension and renal damage. Moreover, Ang II-dependent hypertension alters renal Ang II type 1 & 2 receptors (AT1R & AT2R) and Mas receptor (MasR) expression, and the renal interstitial fluid bradykinin, nitric oxide, and cGMP response to AT1R, AT2R, or BK B2-receptor antagonists. Based on a variety of sources including PubMed, Google Scholar, Scopus, and Science-Direct, in the current review, we will discuss the role of RAS-induced secondary hypertension on the alteration of renal function. 1. Introduction Hypertension is a chronic medical condition known as a major risk for cardiovascular and chronic kidney disease (CKD) [1]. Primary (essential) hypertension does not have an identifiable reason, and 90 to 95% of hypertensive people have essential hypertension, whereas secondary hypertension develops because of an underlying medical condition or disease and accounts for around 5–10% of the cases [2, 3]. In some conditions, kidneys, heart, or arteries and endocrine systems can induce secondary hypertension. Paying attention to secondary hypertension and choosing the appropriate treatment, secondary hypertension will be controlled, and the underlying diseases and the risk of serious complications such as heart disease, kidney failure, and stroke will be limited [2, 3]. The capability of the renin-angiotensin system (RAS) enzymes or receptor antagonists for the treatment of hypertension reveals the important role of RAS. Physiologically, RAS plays a key role in regulating blood pressure (BP) and electrolytes homeostasis while its activation contributes to the pathogenesis of hypertension [4–6]. RAS-dependent hypertension leads to kidney fibrosis and progressive CKD [4, 5], while the latter is the most common cause of secondary hypertension, and it is an independent risk factor for cardiovascular outcomes [5, 7]. The most important RAS component is angiotensin II (Ang II) which acts mostly via two major receptors of type 1 (AT1R) and type 2 (AT2R) [8]. AT1R and AT2R have counterregulatory actions in the cardiovascular and renal systems. The effect of Ang II is mediated primarily by AT1R which is expressed in all the cell types within the kidneys [8, 9]. Renal AT1R stimulation is essential for the development of Ang II-dependent hypertension [10]. Systemic or renal chronic elevation of Ang II levels via AT1R stimulates cellular oxidative injury, reactive oxygen species (ROS) production, apoptosis, vascular inflammation, endothelial dysfunction, chronic heart failure (CHF), and CKD [8, 11, 12]. On the contrary, the AT2R opposes the AT1R, and its expression has a lower degree than AT1R. The physiological action of AT2R is not fully known, but it is known to provide a protective effect against hypertension via augmentation of renal bradykinin (BK), nitric oxide (NO), and cGMP production [13–15]. Ang1-7 is also another key component of the RAS that induces vasodilation via its specific receptor named Mas receptor (MasR). It is documented that AT2R and MasR agonists stimulate NO production in proximal tubules [16]. Ang1-7 has counterregulatory role by opposing AT1R stimulated vasoconstriction and proliferation, and it affects renal functions and hypertension regulation [17, 18]. Ang1-7 also alters renal hemodynamic responses through increasing renal blood flow (RBF) and decreasing renal vascular resistance (RVR) [19]. An increase of Ang II may affect local renal RAS, and due to counterregulatory effect of hypertension and renal injury, it is necessary to understand the exact renal RAS activity-induced hypertension and its effect on renal functions for possible potent therapeutic targets of hypertension therapy. In this review, we investigate the clinical and experimental models of Ang II-induced hypertension as secondary hypertension and the factors affected by Ang II-dependent hypertension. The subjects that underling this article are discussed hereinafter in this paper.(i)Clinical and experimental models in Ang II-induced hypertension(ii)Intrarenal renin expression in Ang II-induced hypertension(iii)Renal and systemic RAS arms modifications in Ang II-induced hypertension(iv)Intrarenal AGT expression and urinary AGT excretion in Ang II-induced hypertension(v)RAS receptors expressions alter in Ang II-induced hypertension(vi)Inflammation in Ang II-induced hypertension(vii)Kidney injury markers in Ang II-induced hypertension and the role of fibrotic and inflammatory factors(viii)Renal interstitial fluid BK, NO, and cGMP responses in Ang II-induced hypertension(ix)Renal function and hemodynamic response in Ang II-induced hypertension 2. Clinical and Experimental Models in Ang II-Induced Hypertension Various forms of experimental and clinical hypertension can be induced by increasing renin formation in the kidney such as renal artery stenosis induced by atherosclerotic plaques, fibromuscular dysplasia, congenital bands, extrinsic compression, vasculitis, and neurofibromatosis [20]. Clinically, a juxtaglomerular cell (JGC) tumor may induce secondary hypertension via renin production [21]. Experimentally, Goldblatt and Grollman’s methods cause Ang II increasing which stimulates the intrarenal and intratubular RAS [22–24]. Three types of hypertension could be performed by Goldblatt methods, including two-kidney one-clip (2K1C), one-kidney one-clip (1K1C), and two-kidney two-clip (2K2C) hypertensions [23–25]. These models of hypertension are performed by constriction of unilateral renal arterial which initiates RAS activation due to an increase in renin secretion [23–25]. In the Grollman model which is also called 2-kidney, 1-shape-of-8-wrap (2K1W), the kidney tissue is wrapped by a shape of 8 ligatures around the kidney and hypertension induced via external compression of renal parenchyma by renin production [14, 24]. 3. Intrarenal Renin Expression in Ang II-Induced Hypertension Renin regulates Ang I generation, and JGCs are the primary source of circulating and intrarenal renin production [26, 27]. The plasma level of renin activity increases immediately after initiation of 2K1C and returns to normal after 28 days [25]. Chronic administration of Ang II increases renin mRNA and protein levels of principal cells in the connecting tubules and collecting ducts [28]. The collecting duct renin enhances in both clipped and unclipped kidneys of Goldblatt hypertensive rats [29]. The upregulation of renin expression in both kidneys in the 2K1C model does not depend on blood pressure level [29]. In addition, the synthesized renin in the collecting duct principal cells is more than JGC with different regulation mechanisms [28, 30] (Figure 1). AT1R and renin mRNAs are coexpressed in JGC while AT1R alters stimulation of renin synthesis [29, 31]. Ang II acts directly on renal JGC via AT1R and its activation suppresses renin synthesis in JGC [31]. However, Ang II itself can augment the collecting duct renin synthesis [32] via AT1R activation directly (the collecting duct renin synthesis is inhibited by AT1R antagonist) [22, 33] (Figure 1).
... Thus, the sodium loading may increase BP only when renal sodium excretion is constrained by ablation of 70% of renal mass or administration of angiotensin or aldosterone. Consequently, the expansion of the extracellular fluid volume initially mediates the rise in BP, despite the reduction in total peripheral resistance, leading predominantly to systolic hypertension [52]. Conversely, the association also might be due to the bidirectional nature of the relationship between creatinine and hypertension [53]. ...
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Introduction Hypertension (HTN) in patients with diabetes mellitus (DM) is a common problem that increases the risk of mortality and morbidity, and lowers the quality of life. Despite the disproportionately high burden of HTN in DM patients, determinants for the comorbidity have not been sufficiently explored. Therefore, this study aimed to identify the determinants of HTN among patients with type 2 diabetes mellitus on follow-up at Tikur Anbessa Specialized Hospital. Methods and materials We conducted a hospital-based unmatched case-control study at Tikur Anbessa Specialized Hospital on 386 randomly selected patients with type 2 diabetes on follow-up (200 cases and 186 controls). We collected data by using a structured interviewer-administered questionnaire and data extraction form. To identify determinants of hypertension, a multivariable binary logistic regression was fitted, and the findings are presented using adjusted odds ratio (AOR) with 95% confidence interval (CI). Results The mean reported age (±SD) of the cases and the controls was 60.3 (±9.9) and 55.3 (±11.3) years, respectively. The eight identified independent determinants of hypertension with AOR [95% CI] were obesity: 2.82 [1.43, 5.57], sedentary activity of ≥4hrs/day: 1.75 [1.10, 2.79], higher stress score: 1.05 [1.01, 1.10], serum creatinine above 1.1 mg/dl: 2.35 [1.13, 4.91], age: 1.05 [1.02, 1.08], being government employee as compared to private workers: 2.18 [1.06, 4.50] and family history of hypertension: 2.11 [1.26, 3.54]. Further, interaction of diabetes duration with insulin use: 1.03 [1.01, 1.07] was also a significant predictor of HTN among DM patients. Conclusion The finding calls for interventions for mitigating these determinants. Further research is needed to examine the interaction between diabetes duration and insulin use.
... This is also corroborated by other studies [15]. The reported prevalence of hypertension, while higher than in normal individuals for all stages of CKD, reaches astronomical proportions of 84.1% in patients with late stages of CKD (Stages 4 & 5) [16]. This mirrors the results obtained in our study. ...
Article
Background The global incidence and prevalence of chronic kidney disease (CKD) is skyrocketing. In Asia, the prevalence of CKD varies from 10%-18%. However, as Asia is largely populated by developing countries with nascent health care systems, there is a dearth of research and data. It is estimated that a large number of cases go unreported. As a result, the exact disease burden remains unclear. The knowledge about risk factors and their proportionate role in CKD is indispensable in regards to patient management and care. Objective The early recognition of the most important risk factors for end-stage renal disease (ESRD) is key to early diagnosis, successful treatment, and general heightened awareness regarding CKD. In developing countries, the provision of medical services, in general, and nephrological services, in particular, is wholly inadequate. The insufficiency of solid and regularly updated data compounds the problem. This research study aims to partake in catering to that need. Methodology A structured questionnaire was used to obtain quantitative and categorical data from 119 ESRD patients in the nephrology ward, Allied Hospital, Faisalabad through non-probability sampling. Socio-demographic profile of the patients and information regarding the presence or absence of risk factors were collected. The resulting dataset was analyzed using R version 3.6.3 (R Foundation for Statistical Computing, Vienna, Austria) for data visualization and descriptive analysis. Results The most common age group for ESRD presentation was 46-60 years (52.1%). Among the 119 ESRD patients, the most frequent risk factor was hypertension with 85.7% of the patients presenting with the condition, followed by diabetes mellitus (DM) in 54.6%, renal calculi in 28.6%, glomerulonephritis (GN) in 31.1%, Family history of CKD in 24.4%, and polycystic kidney disease (PKD) in 5% of the patients. Gender-wise distribution of the patients shows that the proportion of patients with hypertension, renal calculi, and family history of CKD varied very little among the two groups. Conclusion In conclusion, our study has reinforced the existing body of knowledge and brought some fresh evidence regarding the prevalence of risk factors in ESRD to light. Hypertension and DM, together, represent the vast majority of cases with ESRD. However, hypertension far outpaces DM as the leading risk factor. Nephrolithiasis was also present in a considerable minority, with a figure much higher than previously reported. Finally, a relatively younger age group (45-60 years) formed the majority of the ESRD patients which is a concerning development. It points to early progression of CKD to ESRD. Long-term adequate control of these risk factors limits disease progression.
... Until now, it is not clear that DN does not develop in all T2DM patients, even in conditions where long-term glycemia is not well controlled and where lifestyle interventions are present. Having a family history of hypertension or cardiovascular disease also suggests a greater likelihood of developing DN and, based on this fact, the idea that genetic factors may play a central role in predisposing DN is supported [37,38]. The development of genomic examination is an approach to understand the genetic etiology of any complex disease [16,39]. ...
Article
Background There is a continuous rise in the prevalence of Diabetes Mellitus Type 2 (T2DM) worldwide and most patients are unaware of the presence of this chronic disease at the early stages. T2DM is associated with complications related to long-term damage and failure of multiple organ systems caused by vascular changes associated with glycated end products, oxidative stress, mild inflammation, and neovascularization. Among the most frequent complications of T2DM observed in about 20-40% of T2DM patients is Diabetes Nephropathy (DN). Method Literature search was done in view of highlighting the novel application of genomics, proteomics and metabolomics, as the new prospective strategy for predicting DN in T2DM patients. Results The complexity of DN requires a comprehensive and unbiased approach to investigate the main causes of disease and identify the most important mechanisms underlying its development. With the help of evolving throughput technology, rapidly evolving information can now be applied to clinical practice. Discussion DN is also the leading cause of end-stage renal disease, and comorbidity independent of T2DM. In terms of the comorbidity level, DN has many phenotypes; therefore, timely diagnosis is required to prevent these complications. Currently, urine albumin-to-creatinine ratio and estimated glomerular filtration rate (eGFR) are gold standards for assessing glomerular damage and changes in renal function. However, GFR estimation based on creatinine is limited to hyperfiltration status; therefore, this makes albuminuria and eGFR indicators less reliable for early-stage diagnosis of DN. Conclusion The combination of genomics, proteomics, and metabolomics assays as suitable biological systems that can provide new and deeper insights into the pathogenesis of diabetes, as well as to discover prospects for developing suitable and targeted interventions.
... There is strong evidence that HTN accelerates the progression of renal disease. The prevalence of HTN in CKD patients are very high, which may progress to high cardiovascular risk in CKD patients [6,7]. Hence, maintaining target blood pressure(BP) in CKD patient is very essential. ...
Article
Background: ESRD is considered as an important cause of mortality worldwide. Patients with CKD on Hemodialysis treatment is very complex requires additional importance in prescribing antihypertensives and also patients on Hemodialysis have effects on functional state and quality of life (QOL). Objectives: The study aimed to assess prescribing pattern of antihypertensives and to demonstrate QOL in different domains of patients with ESRD underdoing hemodialysis. Materials and Methods: Study comprised of 85 patients with ESRD under hemodialysis conducted in multi-speciality hospital between September 2019 to February 2020.The data was collected from the records and by interviewing patients. Results: The mean age of the study population was 54.76±14.32, 72% were males, hypertension is the common cause of ESRD. Calcium channel blockers are the most commonly prescribed drugs followed by alpha blockers, diuretics, beta blockers, vasodilators etc. Comparing the four domains of ESRD patients, environmental domain was the highest with a mean score of 64.56±19.86while the physical health domain was the lowest with a mean score of55.6±12.60. Conclusion: Calcium channel blockers and alpha blockers are most commonly prescribed antihypertensives. The four domains were signicantly and positively interrelated with moderate to strong relationships
... Among the cardiometabolic perturbations in women with PCOS, increased blood pressure in these women is of primary relevance to disturbances in renal outcomes. Not only is hypertension the leading risk factor for the development of cardiovascular disease, but it is one of the leading causes and consequences of kidney failure [75]. Women with PCOS may be at increased risk of development of renal injuries as reported by marked alterations to kidney function in animal models [34,76]. ...
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SARS-CoV-2, the causative agent of COVID-19, infects host cells using the angiotensin I converting enzyme 2 (ACE2) as its receptor after priming by host proteases, including TMPRSS2. COVID-19 affects multiple organ systems, and male patients suffer increased severity and mortality. Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in reproductive-age women and is characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology. PCOS is associated with obesity and cardiometabolic comorbidities, both being risk factors associated with severe COVID-19 pathology. We hypothesize that elevated androgens in PCOS regulate SARS-CoV-2 entry proteins in multiple tissues increasing the risk for this population. Female mice were treated with dihydrotestosterone (DHT) for 90 days. Body composition was measured by EchoMRI. Fasting glucose was determined by an enzymatic method. mRNA and protein levels of ACE2, Tmprss2, Cathepsin L, Furin, Tmprss4, and Adam17 were quantified by RT-qPCR, Western-blot, or ELISA in tissues, serum, and urine. DHT treatment increased body weight, fat and lean mass, and fasting glucose. Ace2 mRNA was upregulated in the lung, cecum, heart, and kidney, while downregulated in the brain by DHT. ACE2 protein was upregulated by DHT in the small intestine, heart, and kidney. The SARS-CoV-2 priming proteases Tmprss2, Cathepsin L, and Furin mRNA were upregulated by DHT in the kidney. ACE2 sheddase Adam17 mRNA was upregulated by DHT in the kidney, which corresponded with increased urinary ACE2 in DHT treated mice. Our results highlight the potential for increased cardiac, renal, and gastrointestinal dysfunction in PCOS women with COVID-19.
... Hypertension and dyslipidemia are imperative risk factors for cardiovascular disease (CVD) and CKD. [1][2][3][4] Dyslipidemia-associated with elevated total cholesterol (TC), LDL cholesterol (LDLc), lipoprotein-a, plasma triglycerides (TGs), and reduced HDL cholesterol (HDLc) levels-is implicated to increase the incidence of CVD in CKD. 1,3 CVD-related death is the primary cause of mortality in patients with CKD and is highly prevalent in all age groups and in all stages of CKD. ...
Article
Background Dyslipidemia is an important risk factor in CKD. The liver clears triglyceride-rich lipoproteins (TRL) via LDL receptor (LDLR), LDLR-related protein-1 (LRP-1), and heparan sulfate proteoglycans (HSPGs), mostly syndecan-1. HSPGs also facilitate LDLR degradation by proprotein convertase subtilisin/kexin type 9 (PCSK9). Progressive renal failure affects the structure and activity of hepatic lipoprotein receptors, PCSK9, and plasma cholesterol. Methods Uninephrectomy- and aging-induced CKD in normotensive Wistar rats and hypertensive Munich-Wistar-Frömter (MWF) rats. Results Compared with 22-week-old sex- and strain-matched rats, 48-week-old uninephrectomized Wistar-CKD and MWF-CKD rats showed proteinuria, increased plasma creatinine, and hypercholesterolemia (all P <0.05), which were most apparent in hypertensive MWF-CKD rats. Hepatic PCSK9 expression increased in both CKD groups ( P <0.05), with unusual sinusoidal localization, which was not seen in 22-week-old rats. Heparan sulfate (HS) disaccharide analysis, staining with anti-HS mAbs, and mRNA expression of HS polymerase exostosin-1 ( Ext-1 ), revealed elongated HS chains in both CKD groups. Solid-phase competition assays showed that the PCSK9 interaction with heparin-albumin (HS-proteoglycan analogue) was critically dependent on polysaccharide chain length. VLDL binding to HS from CKD livers was reduced ( P <0.05). Proteinuria and plasma creatinine strongly associated with plasma cholesterol, PCSK9, and HS changes. Conclusions Progressive CKD induces hepatic HS elongation, leading to increased interaction with PCSK9. This might reduce hepatic lipoprotein uptake and thereby induce dyslipidemia in CKD. Therefore, PCSK9/HS may be a novel target to control dyslipidemia.