Genetic basis of the impaired renal myogenic response in FHH rats

Abstract

This study examined the effect of substitution of a 2.4-megabase pair (Mbp) region of Brown Norway (BN) rat chromosome 1 (RNO1) between 258.8 and 261.2 Mbp onto the genetic background of fawn-hooded hypertensive (FHH) rats on autoregulation of renal blood flow (RBF), myogenic response of renal afferent arterioles (AF-art), K ϩ channel activity in renal vascular smooth muscle cells (VSMCs), and development of proteinuria and renal injury. FHH rats exhibited poor autoregulation of RBF, while FHH.1BN congenic strains with the 2.4-Mbp BN region exhibited nearly perfect autoregulation of RBF. The diameter of AF-art from FHH rats increased in response to pressure but decreased in congenic strains containing the 2.4-Mbp BN region. Protein excretion and glomerular and interstitial damage were significantly higher in FHH rats than in congenic strains containing the 2.4-Mbp BN region. K ϩ channel current was fivefold greater in VSMCs from renal arterioles of FHH rats than cells obtained from congenic strains containing the 2.4-Mbp region. Sequence analysis of the known and predicted genes in the 2.4-Mbp region of FHH rats revealed amino acid-altering variants in the exons of three genes: Add3, Rbm20, and Soc-2. Quantitative PCR studies indicated that Mxi1 and Rbm20 were differentially expressed in the renal vasculature of FHH and FHH.1BN congenic strain F. These data indicate that transfer of this 2.4-Mbp region from BN to FHH rats restores the myogenic response of AF-art and autoregulation of RBF, decreases K ϩ current, and slows the progression of proteinuria and renal injury. kidney; glomerulosclerosis; chronic renal failure; renal hemodynamics THE FAWN-HOODED HYPERTENSIVE (FHH) rat is a genetic model of hypertension (33) that develops proteinuria, glomerulosclerosis (21,30,37,47), and chronic kidney disease (22,(25)(26)(41)(42). We have previously reported that the development of proteinuria and glomerular injury in FHH rats is associated with an impaired autoregulation of renal blood flow (RBF), glomerular filtration rate (GFR), and glomerular capillary pressure (Pgc) (24,40,43,48). Genetic cosegregation studies identified five quantitative trait loci (QTLs) linked to the development of proteinuria in F2 crosses of FHH and AugustCopenhagen inbred (ACI) rats (4 -5, 36). The rat chromosome (RN) regions are Rf-1 and Rf-2 on RNO1, Rf-3 on RNO3, Rf-4 on RNO14, and Rf-5 on RNO17. The Rf-1 QTL is of particular interest in that it lies within a region that is homologous to an area on human chromosome 10 linked to the development of diabetic nephropathy (19) and end-stage renal disease (18). More recent studies identified a G-to-A mutation in the start codon of Rab38, a gene in the Rf-2 QTL that influences protein trafficking and contributes to the development of proteinuria in FHH rats (32). However, the genes in the Rf-1 region that contribute to the development of proteinuria and renal disease in FHH rats and the mechanisms involved are unknown.We have previously reported that substitution of a 99.4-megabase pair (Mbp) reg...

Comparison of the Development Diabetic Induced Renal Disease in Strains of Goto-Kakizaki Rats

“…Previous studies have indicated that FHH rats develop proteinuria and renal disease as they age and that this is associated with impairment in RBF autoregulation and elevations in glomerular capillary pressure [21–25]. Thus, we hypothesized that perhaps the increased susceptibility of T2DN rats to develop diabetic nephropathy might be due to introgression of a portion of the FHH genome that would alter renal hemodynamics in face of diabetes.…”

Impaired myogenic response of the afferent arteriole contributes to the increased susceptibility to renal disease in Milan normotensive rats

“…We also identified a sequence variant in the coding region of the Add3 gene in FHH rats relative to other strains (Burke et al. ). In our preliminary work, we recognized that this same variant was reported in MNS versus MHS rats, although it was originally assumed that MHS rats carried the mutant allele (Bianchi et al.…”

“…Transfer of a region of chromosome 1 containing 15 genes including the gamma‐adducin or adducin3 (Add3) gene from BN rats rescued the myogenic response of the Af‐Art, autoregulation of RBF and attenuated the development of renal injury (Burke et al. ) in an FHH.1 BN congenic strain. We also identified a sequence variant in the coding region of the Add3 gene in FHH rats relative to other strains (Burke et al.…”

Cerebral Autoregulation in Hypertension and Ischemic Stroke: A Mini Review

“…Functional variants of Add1 have been linked to the development of hypertension in Milan hypertensive rats and humans [79] by altering the localization of plasma membrane and activity of Na+/K+-ATPase [80]. More recently, our lab has identified a genetic variant of Add3 in Fawn Hooded Hypertensive (FHH) rats that are associated with impaired myogenic response and autoregulation of renal and cerebral blood flow [81][82][83]. In addition, knockdown of Add3 expression in both renal and cerebral arteries in normal rats diminishes their myogenic responses ex vivo and enhances BK channels activity [78].…”