Nephron deficit is not required for progressive proteinuria development in the Munich Wistar Frömter rat

Schulz, Angela; Hänsch, Jonna; Kuhn, Karin; Schlesener, Maria; Koßmehl, Peter; Nyengaard, Jens Randel; Wendt, Norbert; Huber, Matthias; Kreutz, Reinhold

doi:10.1152/physiolgenomics.90270.2008

Cited by 25 publications

(40 citation statements)

References 30 publications

(43 reference statements)

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“…141,142 Consomic studies The functional role of both major albuminuria QTLs on RNO6 and RNO8 was confirmed by transfer of either RNO6 or RNO8 from SHR into the MWF background. [138][139][140] Thus, in both single-consomic strains MWF-6 SHR and MWF-8 SHR , the progressive albuminuria observed in aging male and female MWF was significantly ameliorated (Table 2). [138][139][140] Interestingly, the nephron deficit observed in MWF ( À36% vs SHR) was linked to RNO6, since total nephron number was only normalized by replacement of RNO6 but not of RNO8 in consomic strains (Table 2).…”

Section: Munich Wistar Frö Mter Rat Strain Breedingmentioning

confidence: 91%

“…[138][139][140] Thus, in both single-consomic strains MWF-6 SHR and MWF-8 SHR , the progressive albuminuria observed in aging male and female MWF was significantly ameliorated (Table 2). [138][139][140] Interestingly, the nephron deficit observed in MWF ( À36% vs SHR) was linked to RNO6, since total nephron number was only normalized by replacement of RNO6 but not of RNO8 in consomic strains (Table 2). 138,139 Recently, double-consomic studies in MWF-6 SHR 8 SHR by double transfer of SHR-RNO6 and SHR-RNO8 into MWF confirmed a strong synergistic effect between QTL on RNO6 and RNO8, since the albuminuria and associated structural kidney damage phenotypes were completely abolished in the double-consomic strain (Table 2).…”

Section: Munich Wistar Frö Mter Rat Strain Breedingmentioning

confidence: 91%

“…[138][139][140] Interestingly, the nephron deficit observed in MWF ( À36% vs SHR) was linked to RNO6, since total nephron number was only normalized by replacement of RNO6 but not of RNO8 in consomic strains (Table 2). 138,139 Recently, double-consomic studies in MWF-6 SHR 8 SHR by double transfer of SHR-RNO6 and SHR-RNO8 into MWF confirmed a strong synergistic effect between QTL on RNO6 and RNO8, since the albuminuria and associated structural kidney damage phenotypes were completely abolished in the double-consomic strain (Table 2). 143 In a reciprocal single-consomic strain, transfer of MWF-RNO8 into the isolated albuminuria-resistant SHR background caused an induction of albuminuria already under normal conditions, while an increase in structural glomerular damage was only detected after Nx in consomic SHR-8 MWF (Table 2).…”

Section: Munich Wistar Frö Mter Rat Strain Breedingmentioning

confidence: 99%

“…130 Strain characteristics MWF rats develop mild SS spontaneous hypertension, spontaneous albuminuria of early onset, structural renal abnormalities such as an inherited nephron reduction of 30-50%, glomerulosclerosis, reduced podocyte number, renal interstitial fibrosis and endothelial dysfunction. [130][131][132][133][134][135][136][137][138][139] Moreover, a sexual dimorphism leads to a more severe manifestation and progression of albuminuria and subsequent renal failure in males compared with females. 130,133,140 Cosegregation and linkage analyses Schulz et al performed two genome-wide linkage analyses in backcross populations between MWF and a normotensive (Lewis/ FUB ) and a hypertensive (SHR/ FUB ) reference strain and identified overall 11 different QTLs on 10 rat chromosomes including RNO1 (QTL1 and QTL2), RNO4, RNO6-RNO9, RNO12, RNO15, RNO17 and RNOX, which accounted for albuminuria development in MWF (Tables 1 and 5).…”

Section: Munich Wistar Frö Mter Rat Strain Breedingmentioning

confidence: 99%

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Mapping genetic determinants of kidney damage in rat models

Schulz

Kreutz

2012

Hypertens Res

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During the last two decades, significant progress in our understanding of the development of kidney diseases has been achieved by unravelling the mechanisms underlying rare familial forms of human kidney diseases. Due to the genetic heterogeneity in human populations and the complex multifactorial pathogenesis of the disease phenotypes, the dissection of the genetic basis of common chronic kidney diseases (CKD) remains a difficult task. In this regard, several inbred rat models provide valuable complementary tools to uncover the genetic basis of complex renal disease phenotypes that are related to common forms of CKD. In this review, data obtained in nine experimental rat models, including the Buffalo (BUF), Dahl salt-sensitive (SS), Fawn-hooded hypertensive (FHH), Goto-Kakizaki (GK), Lyon hypertensive (LH), Munich Wistar Frömter (MWF), Sabra hypertension-prone (SBH), spontaneously hypertensive rat (SHR) and stroke-prone spontaneously hypertensive rat (SHRSP) inbred strains, that contributed to the genetic dissection of renal disease phenotypes are presented. In this panel of inbred strains, a large number of quantitative trait loci (QTL) linked to albuminuria/proteinuria and other functional or structural kidney abnormalities could be identified by QTL mapping analysis and follow-up studies including consomic and congenic rat lines. The comprehensive exploitation of the genotype-renal phenotype associations that are inherited in this panel of rat strains is suitable for making a significant contribution to the development of an integrated approach to the systems genetics of common CKD. INTRODUCTIONCommon forms of chronic kidney diseases (CKD) represent complex disease phenotypes that are influenced by both environmental and genetic factors. [1][2][3][4][5] Both arterial hypertension and type-2 diabetes mellitus are major contributors to complex CKD, which has a high prevalence in the general human population worldwide affecting B11-15% of individuals in Europe and United States. 6-9 CKD represents as expected a major risk factor for the progression to end-stage renal disease but associates also with an increased risk of cardiovascular morbidity and mortality. 10,11 In addition to the assessment of impaired renal function or glomerular filtration rate, urinary albumin excretion rate (albuminuria) represents another important clinical marker for the evaluation of CKD and cardiovascular risk of patients. [10][11][12][13][14][15] These renal disease phenotypes are also inherited in several inbred rat strains many of which are hypertensive. 16 During the last decades, genetic mapping studies by genome-wide linkage analysis followed by fine mapping of selected quantitative trait loci (QTL) for renal disease phenotypes were reported. Subsequently, studies in consomic and congenic rats were performed to further unravel the genetics of kidney injury in inbred rat strains. For QTL confirmation, consomic strains were generated by transfer of an entire chromosome carrying a QTL from a donor strain into the disease backgro...

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Section: Munich Wistar Frö Mter Rat Strain Breedingmentioning

confidence: 91%

Section: Munich Wistar Frö Mter Rat Strain Breedingmentioning

confidence: 91%

Section: Munich Wistar Frö Mter Rat Strain Breedingmentioning

confidence: 99%

Section: Munich Wistar Frö Mter Rat Strain Breedingmentioning

confidence: 99%

See 2 more Smart Citations

Mapping genetic determinants of kidney damage in rat models

Schulz

Kreutz

2012

Hypertens Res

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“…28 Therefore, we wanted to directly compare twophoton with previous micropuncture-measured GSC A data in the same strain of MW rats and determine the effect of fasting.…”

Section: Glomerular Albumin Permeability Depends On Dietary Status Anmentioning

confidence: 99%

Multiple Factors Influence Glomerular Albumin Permeability in Rats

Sandoval

Wagner

Patel

et al. 2012

Journal of the American Society of Nephrology

141

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Different laboratories recently reported incongruous results describing the quantification of albumin filtration using two-photon microscopy. We investigated the factors that influence the glomerular sieving coefficient for albumin (GSC A ) in an effort to explain these discordant reports and to develop standard operating procedures for determining GSC A . Multiple factors influenced GSC A , including the kidney depth of image acquisition (10-20 mm was appropriate), the selection of fluorophore (probes emitting longer wavelengths were superior), the selection of plasma regions for fluorescence measurements, the size and molecular dispersion characteristics of dextran polymers if used, dietary status, and the genetic strain of rat. Fasting reduced the GSC A in Simonsen Munich Wistar rats from 0.03560.005 to 0.01660.004 (P,0.01). Frömter Munich Wistar rats had a much lower GSC A in both the fed and the fasted states. Finally, we documented extensive albumin transcytosis with vesicular and tubular delivery to and fusion with the basolateral membrane in S1 proximal tubule cells. In summary, these results help explain the previously conflicting microscopy and micropuncture data describing albumin filtration and highlight the dynamic nature of glomerular albumin permeability. Over the past several years, the roles the glomerular filtration barrier and the proximal tubule play in the development of albuminuria have been debated. 1,2 The present textbook model, in which albumin filtration across a normal glomerulus is thought to be minimal, has recently been challenged. A wide array of genetic, molecular, biochemical, and imaging studies are consistent with proximal tubule cells (PTCs) having a role in reclaiming filtered proteins, including albumin, and thus minimizing proteinuria. These studies include the following: knockout mice lacking Na+-H+ exchanger isoform 3 or chloride channel-5; 3 megalin-cubilin complex defects; 4 Rab 38-mediated tubular proteinuria and albuminuria; 5 statin-mediated inhibition of guanosine triphosphatase prenylation with reduced proximal tubule (PT) endocytosis; 4,6-8 mice lacking FcRn, the IgG and albumin receptor; 9,10 and selective PTC injury using D-serine 11 or the selective expression of diphtheria toxin receptor on PTC. 12 In a preliminary communication, Menzel and colleagues showed that PT reabsorption and transcytosis of podocyte produced and secreted albumin labeled with V5 and hemagglutinin tags. 13 Finally, recently published data 14 using advanced scanning electron microscope imaging techniques indicate that the podocyte slit diaphragm has pores that are much larger than previously determined and are of the size required for albumin filtration.The development of in vivo two-photon microscopy has enabled the direct visualization and quantitation of fluorescent compounds as they filter through the glomerulus and are endocytosed by

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Proximal Nephron

Zhuo,

2013

Comprehensive Physiology

169

140

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The kidney plays a fundamental role in maintaining body salt and fluid balance and blood pressure homeostasis through the actions of its proximal and distal tubular segments of nephrons. However, proximal tubules are well recognized to exert a more prominent role than distal counterparts. Proximal tubules are responsible for reabsorbing approximately 65% of filtered load and most, if not all, of filtered amino acids, glucose, solutes, and low molecular weight proteins. Proximal tubules also play a key role in regulating acid-base balance by reabsorbing approximately 80% of filtered bicarbonate. The purpose of this review article is to provide a comprehensive overview of new insights and perspectives into current understanding of proximal tubules of nephrons, with an emphasis on the ultrastructure, molecular biology, cellular and integrative physiology, and the underlying signaling transduction mechanisms. The review is divided into three closely related sections. The first section focuses on the classification of nephrons and recent perspectives on the potential role of nephron numbers in human health and diseases. The second section reviews recent research on the structural and biochemical basis of proximal tubular function. The final section provides a comprehensive overview of new insights and perspectives in the physiological regulation of proximal tubular transport by vasoactive hormones. In the latter section, attention is particularly paid to new insights and perspectives learnt from recent cloning of transporters, development of transgenic animals with knockout or knockin of a particular gene of interest, and mapping of signaling pathways using microarrays and/or physiological proteomic approaches.

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Nephron deficit is not required for progressive proteinuria development in the Munich Wistar Frömter rat

Abstract: Schulz A, Hänsch J, Kuhn K, Schlesener M, Kossmehl P, Nyengaard JR, Wendt N, Huber M, Kreutz R. Nephron deficit is not required for progressive proteinuria development in the Munich Wistar Frömter rat.

Cited by 25 publications

References 30 publications

Mapping genetic determinants of kidney damage in rat models

Mapping genetic determinants of kidney damage in rat models

Multiple Factors Influence Glomerular Albumin Permeability in Rats

Proximal Nephron

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