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

Abstract

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

Mapping genetic determinants of kidney damage in rat models

“…Hence, studies in the FHH, 90,93,95,97 MWF [141][142][143] and SS 53,54 rat models highlighted the role of major susceptibility loci that in concert and genetic interaction with multiple other loci influence renal disease susceptibility (Table 5). Moreover, these models allow the combination of genetic analyses with unlimited gene expression studies, 65,70,150 including timed renal and compartment-specific expression analysis during the onset of renal disease phenotypes such as albuminuria, 143,204 while these experimental algorithms are difficult or impossible to pursue in humans due to the limited access to renal tissue. The comprehensive exploitation of the genotype-renal phenotype associations that are inherited in this panel of rat strains is therefore suitable for making a significant contribution to the development of an integrated approach to the systems genetics of CKD.…”

“…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). 144 Thus, the results demonstrate the independent role of MWF QTL on RNO8 for both albuminuria and structural kidney damage.…”

MicroRNA-324-3p Promotes Renal Fibrosis and Is a Target of ACE Inhibition

“…Polygenetic recessive etiology linked to quantitative trait loci was disclosed in this strain, which was unrelated to BP regulation, 13,14 but the individual gene and related pathway have not been identified as a single factor that may underlie the pathogenesis of renal fibrosis in the MWF strain. This finding raised interest in studying whether post-transcriptional regulation of gene expression could be responsible for abnormal renal phenotype of disease progression.…”

Regulation of podoplanin expression by microRNA-29b associates with its antiapoptotic effect in angiotensin II-induced injury of human podocytes

“…A tissues, including lymphatic endothelial cells and also podocytes [20][21][22]. Recently, PDPN was found to be upregulated in a number of different cancers and identified as a candidate cancer stem cell marker in squamous cell carcinoma [23].…”

“…Moreover, at later time points, when albuminuria had already progressed immunoelectron microscopy analysis showed that foot process effacement coincided with the loss of PDPN, whereas areas in which its expression was retained showed normal ultrastructural morphology [9]. PDPN was suggested to be involved in regulation of cell shape and foot process organization of podocytes possibly via interaction with the actin cytoskeleton [9,20,22]. However, the regulation of PDPN expression and its function in podocytes is not well characterized.…”