Mechanisms of Disease Reversal in Focal and Segmental Glomerulosclerosis

Yang, Haichun; Fogo, Agnes B.

doi:10.1053/j.ackd.2014.04.001

Cited by 20 publications

(12 citation statements)

References 54 publications

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“…This result is consistent with the presence of hypercellularity and enlargement of glomeruli that precede glomerulosclerosis and kidney dysfunction. Similar studies in mice with more advanced disease stages deserve to be carried out to decipher the sequential molecular events leading to glomerulosclerosis, but our results suggest that TGFβ overproduction and its consequences are secondary events following LC-induced proliferation This result is in accordance with studies of human diseases, including diabetic nephropathy (44,45) which showed that glomerulosclerosis at early stages can be reversed with efficient treatment, although this process in humans can take several years. In mouse models, however, the reversibility was demonstrated after short term treatment in diabetic nephropathy (46,47) or hypertension-related glomerulosclerosis (48).…”

Section: Discussionsupporting

confidence: 89%

Glomerulosclerosis and kidney failure in a mouse model of monoclonal immunoglobulin light-chain deposition disease

Bender

Ayala

Bonaud

et al. 2019

Preprint

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Light chain deposition disease (LCDD) is a rare disorder characterized by glomerular and peritubular amorphous deposits of a monoclonal immunoglobulin (Ig) light chain (LC), leading to nodular glomerulosclerosis and nephrotic syndrome. We developed a transgenic model using site-directed insertion of the variable domain of a pathogenic human LC gene into the mouse Ig kappa locus, ensuring its production by all plasma cells. High free LC levels were achieved after backcrossing with mice presenting increased plasma cell differentiation and no Ig heavy chain (HC) production. Our mouse model recapitulates the characteristic features of LCDD, including progressive glomerulosclerosis, nephrotic-range proteinuria and finally, kidney failure. The variable domain of the LC bears alone the structural properties involved in its pathogenicity. RNA sequencing conducted on plasma cells demonstrated that LCDD LC induces endoplasmic reticulum stress, likely accounting for the high efficiency of proteasome inhibitor-based therapy. Accordingly, reduction of circulating pathogenic LC was efficiently achieved and not only preserved renal function, but partially reversed kidney lesions. Finally, transcriptome analysis of pre-sclerotic glomeruli revealed that proliferation and extracellular matrix remodelling represented the first steps of glomerulosclerosis, paving the way for future therapeutic strategies in LCDD and other kidney diseases featuring diffuse glomerulosclerosis, particularly diabetic nephropathy. Introduction : Monoclonal gammopathies of renal significance (MGRS) are characterized by renal lesions due to monoclonal immunoglobulins produced by a non-malignant B or plasma cell clone (1). Depending on the type and structural properties of the Ig, they comprise tubulopathies caused by LC accumulating in the proximal or distal tubules, or glomerulopathies, most frequently AL amyloidosis and Randall-type monoclonal Ig deposition disease (MIDD) (2). MIDD are characterized by linear amorphous deposits of a monoclonal LC (LCDD) or a truncated HC (HCDD) along the tubular and glomerular basement membranes (BMs), around arteriolar myocytes and in the mesangium, eventually leading to diabetic-like nodular glomerulosclerosis. Clinical manifestations include glomerular proteinuria with progressive kidney failure (3-5). In LCDD, the most frequent form of MIDD, involved LCs are mostly of the kappa isotype, with a striking overrepresentation of the Vk4 variable domain characterized by a long CDR1. Other peculiarities of LCDD LCs are due to somatic hypermutations and include polar to hydrophobic amino-acids replacements, small truncations or abnormal glycosylations (3, 4, 6-10). Moreover, LCDD LCs are characterized by the constant high isoelectric point (pI) of their V domain compared to LCs involved in AL amyloidosis (11).This feature was also confirmed in HCDD and could account for the high avidity of positively charged LCs for anionic heparan sulfates of basement membranes (5). However, little is known about the pathogenic mechanisms i...

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Section: Discussionsupporting

confidence: 89%

Glomerulosclerosis and kidney failure in a mouse model of monoclonal immunoglobulin light-chain deposition disease

Bender

Ayala

Bonaud

et al. 2019

Preprint

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“…The histopathological improvement is in accordance as in [11] which showed that administration of ACE inhibitors can improve the histopathology of glomerulosclerosis by increasing the amount of plasmin by decreasing the expression of PAI-1 (Plasminogen Activator Inhibitor-1) which occurs due to a decrease in angiotensin II. The increase in plasmin levels will increase degradation of the extracellular matrix and lyse fibrin (matrix remodeling).…”

Section: Fig 2 Diastolic Blood Pressure Linear Test Graphsupporting

confidence: 85%

“…Glucocorticoids which interact with glucocorticoid receptors in smooth and endothelial blood vessels which will increase the activation of AT-1 receptors. Angiotensin II which binds to AT-1 and At-2 will induce aldosterone synthesis which will increase in plasma volume and blood pressure [9]- [11].…”

Section: Fig 1 Systolic Blood Pressure Linear Test Graphmentioning

confidence: 99%

“…Bidara leaf is used in the treatment of indigestion, fever, liver damage and lung disease, but research on bidara leaf is still small [8]- [9]. Leaf bidara contains several biochemical active ingredients such as alkaloids, saponins, tannins, flavonoids, and terpenoids have their respective mechanisms in repairing and preventing the occurrence of glomerulosclerosis [10,11,12].…”

Section: Introductionmentioning

confidence: 99%

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The Role of Bidara Leaf Extract (Ziziphus Mauritiana) on the Prevention of Renal Hypertension in Wistar Strain Rats

2020

IJITEE

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 Abstract: Hypertension is ranked the fourth highest disease in the word. Glomerulosclerosis is the initial lesion from kidney failure in patient with hypertension. Bidara leaves have active flavonoid such as saponins and tannins are thought to prevent an increase in blood pressure and repair glomerulosclerosis. This study to prove the effect of bidara leaf extract to decrease hypertension and to prevent glomerulosclerosis. This study was true experimental with Pre and Post Test Control Group Design. This study used male white rats wistar strain. Sample divided into 5 groups (positive group, treatment group with 3 leveled dose, and medicine-control group) and were being observed in 28 days. Hypertension was measured using tail cuff blood pressure. Glomerulus observed randomly with light microscope in 5 different field of view with 400x magnification and scoring by Sclerosis Index (SI). In the linear regression test had R 2 = 0,332 for systolic blood pressure and R 2 = 0,609 for diastolic blood pressure. For glomerulosclerosis we found that the highest SI (369,69) was positive control group, while the lowest SI (84,09) was the group with a dose 400mg/kg/day. Bidara leaves extract have a significant effect on reduce hypertension and glomerulosclerosis.

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“…Glomerulosclerosis (GS) is an inflammatory disease. The pathogenic mechanisms include dysregulation of lipid metabolism, production of inflammatory mediators, mesangial cell (MC) proliferation, intra‐ and extracellular lipid accumulation, and matrix production . However, the mechanisms are still not fully elucidated.…”

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confidence: 99%

Endoplasmic reticulum stress participates in inflammation‐accelerated, lipid‐mediated injury of human glomerular mesangial cells

et al. 2017

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Mechanisms of Disease Reversal in Focal and Segmental Glomerulosclerosis

Cited by 20 publications

References 54 publications

Glomerulosclerosis and kidney failure in a mouse model of monoclonal immunoglobulin light-chain deposition disease

Glomerulosclerosis and kidney failure in a mouse model of monoclonal immunoglobulin light-chain deposition disease

The Role of Bidara Leaf Extract (Ziziphus Mauritiana) on the Prevention of Renal Hypertension in Wistar Strain Rats

Endoplasmic reticulum stress participates in inflammation‐accelerated, lipid‐mediated injury of human glomerular mesangial cells

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