Reduction of proteinuria in adriamycin-induced nephropathy is associated with reduction of renal kidney injury molecule (Kim-1) over time

Kramer, Andrea B.; Timmeren, Mirjan M. van; Schuurs, Theo A.; Vaidya, Vishal S.; Bonventre, Joseph V.; Goor, Harry van; Navis, Gerjan

doi:10.1152/ajprenal.00541.2007

Cited by 77 publications

(70 citation statements)

References 37 publications

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“…11 In contrast, transfer of both chromosomes in double-consomic animals as reported here leads to a complete reduction of glomerular structural damage and tubular damage as reflected by Kim-1 expression. 15 This occurred on the background of similar blood pressures compared with MWF, indicating an interaction between genes on RNO6 and RNO8 influencing the development of renal damage as well.…”

Section: Discussionmentioning

confidence: 78%

Elimination of Severe Albuminuria in Aging Hypertensive Rats by Exchange of 2 Chromosomes in Double-Consomic Rats

Schulz

IJpelaar

et al. 2011

Hypertension

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Abstract-The inherited nephron deficit and progressive albuminuria development observed in hypertensive MunichWistar Frömter (MWF) rats are influenced by quantitative trait loci on rat chromosome (RNO) 6 and RNO8. Previous studies in young MWF rats suggested that the nephron deficit represents a cause for glomerular hypertrophy preceding onset of albuminuria at 8 weeks and demonstrated a simultaneous induction of the podocyte stress marker desmin and podoplanin loss in podocytes. Key Words: genetics Ⅲ albuminuria Ⅲ glomerular damage Ⅲ podocyte Ⅲ consomic rat A lbuminuria is an important independent predictor for progression of both renal and cardiovascular disease and also of mortality risk in patients with hypertensive diabetes mellitus and even in the general population. 1,2 Previous reports have shown that the genetic predisposition for development of albuminuria is complex and multifactorial. [3][4][5][6][7] The Munich Wistar Frömter (MWF) rat is a suitable animal model to investigate the genetic and molecular mechanisms related to early development of albuminuria. MWF rats demonstrate an inherited nephron deficit and mild hypertension and develop at young age spontaneous albuminuria followed by progressive proteinuria in aging animals. 8,9 In previous studies we have shown that increased urinary albumin excretion (UAE) in MWF rats is largely determined by quantitative trait loci on rat chromosome (RNO) 6 and RNO8, respectively. 10,11 In these studies we used the spontaneously hypertensive rat (SHR) as a contrasting reference strain with lowgrade UAE 12 and transferred in separate experiments either the entire chromosome 6 or 8 from SHRs into the MWF genetic background. The resulting consomic rat strains, that is, , demonstrated both a marked suppression of early albuminuria development compared with the MWF strain, thus providing evidence for the functional relevance of genes on RNO6 and RNO8 for albuminuria, respectively. 10,11 IJpelaar et al 13 showed previously that onset of albuminuria in young MWF animals is already preceded by glomerular hypertrophy and coincided with focal and segmental loss of podoplanin and de novo expression of desmin in affected podocytes when compared with SHRs. 13 The genes coding for desmin and podoplanin map to RNO9 and RNO5 and can, therefore, be ruled out as positional candidate genes for the 2 important albuminuria quantitative trait loci on RNO6 and

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Section: Discussionmentioning

confidence: 78%

Elimination of Severe Albuminuria in Aging Hypertensive Rats by Exchange of 2 Chromosomes in Double-Consomic Rats

Schulz

IJpelaar

et al. 2011

Hypertension

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“…1310 6 Dil-labeled apoptotic thymocytes or 50 mg/ml ox-LDL was added to confluent epithelial cell layers. After 2 hours at 37°C, cells were washed vigorously five times with ice-cold PBS/0.1% sodium azide (without Mg 2+ /Ca 2+ ) to remove bound and uningested apoptotic cells or debris.…”

Section: Phagocytosis Assaysmentioning

confidence: 99%

“…[2][3][4] KIM-1 clears the tubule lumen of debris following AKI, aiding in nephron repair and tissue remodeling. KIM-1 is also upregulated in a variety of animal models of CKD, including protein overload nephropathy, 5 adriamycin-induced nephropathy, 6 angiotensin II-induced renal damage, 7 and murine polycystic kidney disease, 8 where it colocalizes with areas of fibrosis and inflammation. 9 It is upregulated in human CKD 10 and its expression correlates directly with interstitial fibrosis in human allografts.…”

mentioning

confidence: 99%

Mammalian Target of Rapamycin Mediates Kidney Injury Molecule 1-Dependent Tubule Injury in a Surrogate Model

Yin¹,

Naini²,

Chen³

et al. 2015

JASN

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Kidney injury molecule 1 (KIM-1), an epithelial phagocytic receptor, is markedly upregulated in the proximal tubule in various forms of acute and chronic kidney injury in humans and many other species. Whereas acute expression of KIM-1 has adaptive anti-inflammatory effects, chronic expression may be maladaptive in mice. Here, we characterized the zebrafish Kim family, consisting of Kim-1, Kim-3, and Kim-4. Kim-1 was markedly upregulated in kidney after gentamicin-induced injury and had conserved phagocytic activity in zebrafish. Both constitutive and tamoxifen-induced expression of Kim-1 in zebrafish kidney tubules resulted in loss of the tubule brush border, reduced GFR, pericardial edema, and increased mortality. Kim-1-induced kidney injury was associated with reduction of growth of adult fish. Kim-1 expression led to activation of the mammalian target of rapamycin (mTOR) pathway, and inhibition of this pathway with rapamycin increased survival. mTOR pathway inhibition in KIM-1-overexpressing transgenic mice also significantly ameliorated serum creatinine level, proteinuria, tubular injury, and kidney inflammation. In conclusion, persistent Kim-1 expression results in chronic kidney damage in zebrafish through a mechanism involving mTOR. This observation predicted the role of the mTOR pathway and the therapeutic efficacy of mTOR-targeted agents in KIM-1-mediated kidney injury and fibrosis in mice, demonstrating the utility of the Kim-1 renal tubule zebrafish models.

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“…The extracellular KIM-1 Ig variable domain binds and internalizes oxidized lipid as well as phosphatidylserine exposed on the outer leaflet of luminal apoptotic cells (13,14), thereby aiding in nephron repair and tissue remodeling through phagocytosis of cells and debris (15). KIM-1 is expressed in CKD (16)(17)(18)(19)(20) where it colocalizes with areas of fibrosis and inflammation (21), and its expression correlates directly with interstitial fibrosis in human allografts (22). Increased urinary KIM-1 is an independent predictor of long-term renal graft loss and is also elevated in human nondiabetic, proteinuric CKD (23,24).…”

Section: Introductionmentioning

confidence: 99%

Chronic epithelial kidney injury molecule-1 expression causes murine kidney fibrosis

Humphreys

Xu²,

Sabbisetti³

et al. 2013

J. Clin. Invest.

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308

253

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Acute kidney injury predisposes patients to the development of both chronic kidney disease and end-stage renal failure, but the molecular details underlying this important clinical association remain obscure. We report that kidney injury molecule-1 (KIM-1), an epithelial phosphatidylserine receptor expressed transiently after acute injury and chronically in fibrotic renal disease, promotes kidney fibrosis. Conditional expression of KIM-1 in renal epithelial cells (Kim1 RECtg ) in the absence of an injury stimulus resulted in focal epithelial vacuolization at birth, but otherwise normal tubule histology and kidney function. By 4 weeks of age, Kim1 RECtg mice developed spontaneous and progressive interstitial kidney inflammation with fibrosis, leading to renal failure with anemia, proteinuria, hyperphosphatemia, hypertension, cardiac hypertrophy, and death, analogous to progressive kidney disease in humans. Kim1 RECtg kidneys had elevated expression of proinflammatory monocyte chemotactic protein-1 (MCP-1) at early time points. Heterologous expression of KIM-1 in an immortalized proximal tubule cell line triggered MCP-1 secretion and increased MCP-1-dependent macrophage chemotaxis. In mice expressing a mutant, truncated KIM-1 polypeptide, experimental kidney fibrosis was ameliorated with reduced levels of MCP-1, consistent with a profibrotic role for native KIM-1. Thus, sustained KIM-1 expression promotes kidney fibrosis and provides a link between acute and recurrent injury with progressive chronic kidney disease.

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Reduction of proteinuria in adriamycin-induced nephropathy is associated with reduction of renal kidney injury molecule (Kim-1) over time

Cited by 77 publications

References 37 publications

Elimination of Severe Albuminuria in Aging Hypertensive Rats by Exchange of 2 Chromosomes in Double-Consomic Rats

Elimination of Severe Albuminuria in Aging Hypertensive Rats by Exchange of 2 Chromosomes in Double-Consomic Rats

Mammalian Target of Rapamycin Mediates Kidney Injury Molecule 1-Dependent Tubule Injury in a Surrogate Model

Chronic epithelial kidney injury molecule-1 expression causes murine kidney fibrosis

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