Lanosterol Synthase Genetic Variants, Endogenous Ouabain, and Both Acute and Chronic Kidney Injury

Hypertension, diabetes and obesity, along with genetic predisposition, contribute to the growing number of chronic kidney disease patients. Our novel congenic model [S.SHR(11)] was developed through genetic modification of the Dahl salt-sensitive (S) rat, a model of hypertension related renal disease. The S.SHR(11) strain exhibits accelerated kidney injury compared to the already highly susceptible S rat. On either a low or high-salt diet, the S.SHR(11) model predominately exhibited more tubulointerstitial fibrosis compared to the S rat (17.1±1.29% vs. 12.9±1.22%). Increased α-SMA and macrophage infiltration was also observed. The S and S.SHR(11) had similar blood pressure (week 12), despite an early reduction in renal function in the S.SHR(11); however at an advanced age the S.SHR(11) demonstrated significantly higher blood pressure than the S (215±6.6 mm Hg vs. 183±5.9, respectively). This suggests that increased kidney injury is driving the development of hypertension later in life. Since these two animal models are identical with exception of chromosome 11, the causative genetic variants contributing to decreased renal function must reside within this region. The Dahl S and SHR genomes have been sequenced; this data provides a catalog of all the genetic variants between the two models. The 95% confidence interval of the genomic locus contains 28 non-synonymous SNP, with 15 of these SNP occurring within only three genes: Retnlg , Trat1 and Myh15. Two of these genes, Retnlg and Trat1, are known to play a role in immune response leading to our hypothesis that genetic variants in these genes alter protein function and lead to an increased immune response. Bone marrow transplant studies have been initiated to test our hypothesis and preliminary data shows that S rats who receive S.SHR(11) bone marrow have kidney function measurements similar to the S.SHR(11). The sequencing information has also lead to the development of nine new, more refined congenic strains. Through functional analysis of these new congenic animals, identification of the causative genetic variations will be expedited. In summary, we are employing a model of accelerated kidney disease to identify genes or genetic variants responsible for reduced kidney function and hypertension.

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Metastatische pulmonale calcificaties als zeldzame oorzaak van matglasopaciteiten op een CT-scan

Tijdschrift voor Geneeskunde ◽

10.47671/tvg.77.21.081 ◽

2021 ◽

Author(s):

I. CARPENTIER ◽

E. PEETERS ◽

B. VANZIELEGHEM

Keyword(s):

Correct Diagnosis ◽

Kidney Injury ◽

Lung Damage ◽

Ground Glass ◽

Literature Overview ◽

Chronic Kidney Injury ◽

Patient’S History ◽

Pulmonary Calcifications ◽

Metastatic Pulmonary Calcification

Metastatic pulmonary calcification: a case report and literature overview Ground-glass opacities have a broad differential diagnosis, including infectious, metabolic, inflammatory and malignant causes. This case presents an underdiagnosed entity of dense ground-glass opacities, namely metastatic pulmonary calcifications (MPC). This is a benign metabolic disease characterised by the deposition of calcium in the lungs, mostly described in patients with chronic kidney injury and secondary hyperparathyroidism. The majority of the patients require no treatment, but in some cases it may lead to irreversible lung damage. Clinical and radiological features, as well as the patient’s history, are crucial to make a correct diagnosis since MPC has a relatively specific appearance on imaging. This case study discusses the medical history and imaging appearance of a 44-year-old woman with MPC, followed by a literature overview.

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Urinary angiotensinogen as a biomarker for acute to chronic kidney injury transition – prognostic and mechanistic implications

Clinical Science ◽

10.1042/cs20180795 ◽

2018 ◽

Vol 132 (21) ◽

pp. 2383-2385 ◽

Cited By ~ 1

Author(s):

Katie L. Connor ◽

Laura Denby

Keyword(s):

Kidney Injury ◽

Renin Angiotensin System ◽

Ischaemia Reperfusion Injury ◽

Angiotensin System ◽

Urinary Angiotensinogen ◽

Tubular Necrosis ◽

Ischaemia Reperfusion ◽

Structural Recovery ◽

Chronic Kidney Injury ◽

Injury Model

Accurate biomarkers that both predict the progression to, and detect the early stages of chronic kidney disease (CKD) are lacking, resulting in difficulty in identifying individuals who could potentially benefit from targeted intervention. In a recent issue [Clinical Science (2018) 132, 2121–2133], Cui et al. examine the ability of urinary angiotensinogen (uAGT) to predict the progression of acute kidney injury (AKI) to CKD. They principally employ a murine ischaemia reperfusion injury model to study this and provide data from a small prospective study of patients with biopsy proven acute tubular necrosis. The authors suggest that uAGT is a dynamic marker of renal injury that could be used to predict the likelihood of structural recovery following AKI. Here we comment on their findings, exploring the clinical utility of uAGT as a biomarker to predict AKI to CKD transition and perhaps more controversially, to discuss whether the early renin–angiotensin system blockade following AKI represents a therapeutic target.

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Editorial (Thematic Issue: Acute and Chronic Kidney Injury: From Basic Science to Clinical Practice)

Current Medicinal Chemistry ◽

10.2174/092986732319160719183122 ◽

2016 ◽

Vol 23 (19) ◽

pp. 1940-1940

Author(s):

Milica Prostran

Keyword(s):

Clinical Practice ◽

Basic Science ◽

Kidney Injury ◽

Thematic Issue ◽

Chronic Kidney Injury

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Activation of hypoxia-sensing pathways promotes renal ischemic preconditioning following myocardial infarction

AJP Renal Physiology ◽

10.1152/ajprenal.00476.2020 ◽

2021 ◽

Author(s):

Andrew S Terker ◽

Kensuke Sasaki ◽

Juan Pablo Arroyo ◽

Aolei Niu ◽

Suwan Wang ◽

...

Keyword(s):

Myocardial Infarction ◽

Ischemic Preconditioning ◽

Renal Injury ◽

Cardiac Injury ◽

Kidney Injury ◽

Cardiorenal Syndrome ◽

Experimental Myocardial Infarction ◽

Common Mechanism ◽

Cardiac Damage ◽

Chronic Kidney Injury

Ischemic heart disease is the leading cause of death worldwide and is frequently comorbid with chronic kidney disease. Physiological communication is known to occur between the heart and the kidney and primary dysfunction in either organ can induce dysfunction in the other, a clinical entity known as cardiorenal syndrome, but mechanistic details are lacking. Here, we used a model of experimental myocardial infarction (MI) to test effects of chronic cardiac ischemia on acute and chronic kidney injury. Surprisingly, chronic cardiac damage protected animals from subsequent acute ischemic renal injury, an effect that was accompanied by evidence of chronic kidney hypoxia. The protection observed post-MI was similar to protection observed in a separate group of healthy animals housed in ambient hypoxic conditions prior to kidney injury, suggesting a common mechanism. There was evidence that chronic cardiac injury activates renal hypoxia-sensing pathways. Increased renal abundance of several glycolytic enzymes following MI suggested a shift towards anaerobic glycolysis may confer renal ischemic preconditioning. In contrast, effects on chronic renal injury followed a different pattern with post-MI animals displaying worsened chronic renal injury and fibrosis. These data show that while chronic cardiac injury following MI protected against acute kidney injury via activation of hypoxia-sensing pathways, it worsened chronic kidney injury. The results further our understanding of cardiorenal signaling mechanisms and have implications for the treatment of heart failure patients with associated renal disease.

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Abstract 188: Loss of Renal Prolyl Carboxypeptidase in Mice With Chronic Kidney Disease

Hypertension ◽

10.1161/hyp.62.suppl_1.a188 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Orly Leiva ◽

Khalid M Elased ◽

Mariana Morris ◽

Nadja Grobe

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Protein Expression ◽

Western Blot ◽

Kidney Injury ◽

Renin Angiotensin System ◽

Left Renal Artery ◽

Renal Tubules ◽

Ang Ii ◽

Chronic Kidney Injury

There are 26 million adults with chronic kidney disease (CKD) in the U.S. and the incidence continues to increase. It is well documented that the activation of the renin angiotensin system and the elevated formation of angiotensin (Ang) II both contribute to renal pathophysiology in CKD. Emerging evidence suggests that the Ang II degrading protease prolyl carboxypeptidase (PCP) is renoprotective. Thus, we investigated protein expression and activity of renal PCP using immunofluorescence, western blot and mass spectrometry in a mouse model of CKD. Renal injury in male C57Bl6 mice was caused by constriction of the left renal artery using silver clips (2K1C-method). Blood pressure measurements by radiotelemetry revealed a significant increase of 36.1 ± 3.9 mm Hg in 2K1C animals compared with control animals 1 week after clip placement (p<0.0001). Using immunofluorescence and confocal microscopy, PCP was localized in the Bowman’s capsule of the glomerulus and in proximal and distal renal tubules. Western blot analysis showed PCP was significantly reduced in clipped 2K1C kidneys compared to unclipped kidneys of the 2K1C mice or compared to control mice (clipped 0.04 ± 0.02 vs unclipped 0.58 ± 0.16 vs control 0.65 ± 0.18, p < 0.05). In addition, renal PCP enzyme activity was found to be markedly reduced in 2K1C kidneys as assessed by mass spectrometric based enzyme assays (clipped 37.1 ± 4.3 pmol Ang-(1-7)/h/μg vs unclipped 77.3 ± 12.3 pmol Ang-(1-7)/h/μg vs control 120.7 ± 14.7 pmol Ang-(1-7)/h/μg, p < 0.01). In contrast, protein expression of prolyl endopeptidase, another enzyme capable of converting Ang II into Ang-(1-7), was not affected. Notably, renal pathologies were exacerbated in the 2K1C model as revealed by a significant increase in mesangial expansion (clipped 34.6 ± 3.1 vs unclipped 52.1 ± 4.0 vs control 1.2 ± 2.1, p < 0.0001) and renal fibrosis (clipped 57.5 ± 0.9 vs unclipped 33.0 ± 0.7 vs control 3.3 ± 0.2, p < 0.0001). Results suggest that PCP is suppressed in chronic kidney injury and that this downregulation may attenuate renoprotective effects via impaired Ang II degradation by PCP. Therefore, Ang II processing by PCP may have clinical implications in patients with renal pathologies.

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