Chromosomes 18 and X are quantitative trait loci for nephrotic-range proteinuria in rats

Abstract

Numerous cellular and molecular perturbations have been studied to elucidate the pathogenic mechanisms underlying nephrotic-range proteinuria, which may in turn shed light on disease-specific mechanisms. We have analyzed the publicly available data from the PhysGen partial panel of consomic rats to determine whether there are quantitative trait loci that associate with nephroticrange proteinuria. As of this writing, consomic rat strains subjected to the renal protocol have been bred by the Program for Genomic Applications for 15 of the 22 rat chromosomes for both genders, predominantly with the Brown-Norway (BN) and Dahl salt-sensitive (SS) strains as parents. We defined chromosomes of interest as consomic SS-xBN strains whose phenotype measurements differed significantly from SS but not BN strains, stratified by gender. We filtered and clustered differentially expressed genes by function in renal tissue from relevant strains. Proteinuria was significantly higher in male SS vs. male SS-18BN, and it was significantly higher in male SS vs. female SS. Functional clustering of differentially expressed genes yielded two specific functional clusters: apoptosis (p=0.022) and angiogenesis (p=0.046). Gene expression profiles demonstrated differential expression of apoptotic and angiogenic genes. However, TUNEL stains of renal tissue showed no significant difference in the number of apoptotic nuclei. We conclude that chromosomes 18 and X are quantitative trait loci for nephrotic-range proteinuria in rats.

Genetic Background Specific Hypoxia Resistance in Rat is Correlated with Balanced Activation of a Cross-Chromosomal Genetic Network Centering on Physiological Homeostasis

“…Moreover, through the analysis on chromosome representation index, I made the observation that to some extent, cis-effect somewhat prevailed in genetic background effects (Set C genes), whereas trans-effect became dominant under hypoxia condition (Set B genes). This observation is partially consensus to previous reports (Schachter et al, 2005 ; Liang et al, 2008 ). Together, this and other findings showed that the expression profile variability under hypoxia was the result of the transactions of CS chromosome polymorphisms through complex interaction with polymorphisms distributed in the whole genome.…”

Mapping genetic determinants of kidney damage in rat models

“…66 For consomic studies, the animals were fed diets with different salt content, for example, normal (0.4%) or high-salt diets (4% or 8% NaCl) and protein compositions, and were also additionally exposed to hypoxia. 55,67,68 Collectively, it was demonstrated in male rats that proteinuria and/or albuminuria was significantly attenuated by transfer of RNO1, RNO5-8, RNO11, RNO13, RNO16, RNO18 and RNOY from BN into SS (Table 2). 55,67,68 Interestingly, in corresponding females introgression of each BN chromosome resulted in a significant reduction of proteinuria and/or albuminuria with the exception of RNO3, RNO15, RNO17 and RNOX (Table 2).…”

“…55,67,68 Collectively, it was demonstrated in male rats that proteinuria and/or albuminuria was significantly attenuated by transfer of RNO1, RNO5-8, RNO11, RNO13, RNO16, RNO18 and RNOY from BN into SS (Table 2). 55,67,68 Interestingly, in corresponding females introgression of each BN chromosome resulted in a significant reduction of proteinuria and/or albuminuria with the exception of RNO3, RNO15, RNO17 and RNOX (Table 2). 55,68 A sexual dimorphism with higher proteinuria levels in male compared with female SS rats was reported in another study and related to a functional effect of RNOX on proteinuria although this has not been confirmed and documented, for example, by data obtained in consomic strains.…”

“…55,68 A sexual dimorphism with higher proteinuria levels in male compared with female SS rats was reported in another study and related to a functional effect of RNOX on proteinuria although this has not been confirmed and documented, for example, by data obtained in consomic strains. 67 Structural glomerular injury was significantly influenced by RNO1 in male rats (Table 2). 68 In addition, transfer of BN-RNO13 (containing the renin gene) into consomic SS.BN13 ameliorated proteinuria levels, medullary interstitial fibrosis, glomerulosclerosis and tubular necrosis in response to high salt (4% NaCl; Table 2).…”