Increased susceptibility to kidney injury by transfer of genomic segment from SHR onto Dahl S genetic background.

The Dahl salt-sensitive (S) rat is a widely studied model of salt-sensitive hypertension and develops proteinuria, glomerulosclerosis, and renal interstitial fibrosis. An earlier genetic analysis using a population derived from the S and spontaneously hypertensive rat (SHR) identified eight genomic regions linked to renal injury in the S rat and one protective locus on chromosome 11. The "protective" locus in the S rat was replaced with the SHR genomic segment conferring "susceptibility" to kidney injury. The progression of kidney injury in the S.SHR(11) congenic strain was characterized in the present study. Groups of S and S.SHR(11) rats were followed for 12 wk on either a low-salt (0.3% NaCl) or high-salt (2% NaCl) diet. By week 12 (low-salt), S.SHR(11) demonstrated a significant decline in kidney function compared with the S. Blood pressure was significantly elevated in both strains on high salt. Despite similar blood pressure, the S.SHR(11) exhibited a more significant decline in kidney function compared with the S. The decline in S.SHR(11) kidney function was associated with more severe kidney injury including tubular loss, immune cell infiltration, and tubulointerstitial fibrosis compared with the S. Most prominently, the S.SHR(11) exhibited a high degree of medullary fibrosis and a significant increase in renal vascular medial hypertrophy. In summary, genetic modification of the S rat generated a model of accelerated renal disease that may provide a better system to study progression to renal failure as well as lead to the identification of genetic variants involved in kidney injury.

[1]  Y. Liu,et al.  MiR-382 targeting of kallikrein 5 contributes to renal inner medullary interstitial fibrosis. , 2012, Physiological genomics.

[2]  R. Roman,et al.  Role of medullary blood flow in the pathogenesis of renal ischemia–reperfusion injury , 2012, Current opinion in nephrology and hypertension.

[3]  A. Cowley,et al.  Renal injury in angiotensin II+L-NAME-induced hypertensive rats is independent of elevated blood pressure. , 2011, American journal of physiology. Renal physiology.

[4]  M. Garrett,et al.  Heterogeneous stock rats: a new model to study the genetics of renal phenotypes. , 2010, American journal of physiology. Renal physiology.

[5]  Robert R. Quinn,et al.  Relation between kidney function, proteinuria, and adverse outcomes. , 2010, JAMA.

[6]  M. Garrett,et al.  Investigating the effect of genetic background on proteinuria and renal injury using two hypertensive strains. , 2009, American journal of physiology. Renal physiology.

[7]  L. Lerman,et al.  Angiogenesis in the kidney: a new therapeutic target? , 2009, Current opinion in nephrology and hypertension.

[8]  S. Ledbetter,et al.  Protective effect of 20-HETE analogues in experimental renal ischemia reperfusion injury. , 2009, Kidney international.

[9]  V. Bellizzi,et al.  [Prevalence of chronic kidney disease]. , 2008, Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia.

[10]  A. Go,et al.  The risk of acute renal failure in patients with chronic kidney disease. , 2008, Kidney international.

[11]  S. Waikar,et al.  Diagnosis, epidemiology and outcomes of acute kidney injury. , 2008, Clinical journal of the American Society of Nephrology : CJASN.

[12]  B. Psaty,et al.  Cardiovascular risk factors and incident acute renal failure in older adults: the cardiovascular health study. , 2008, Clinical journal of the American Society of Nephrology : CJASN.

[13]  J. Coresh,et al.  Prevalence of chronic kidney disease in the United States. , 2007, JAMA.

[14]  M. Garrett,et al.  Dissection of a genetic locus influencing renal function in the rat and its concordance with kidney disease loci on human chromosome 1q21. , 2007, Physiological genomics.

[15]  Takefumi Mori,et al.  Enhanced Superoxide Production in Renal Outer Medulla of Dahl Salt-Sensitive Rats Reduces Nitric Oxide Tubular-Vascular Cross-Talk , 2007, Hypertension.

[16]  Tom Greene,et al.  Surrogate end points for clinical trials of kidney disease progression. , 2006, Clinical journal of the American Society of Nephrology : CJASN.

[17]  M. Garrett,et al.  Genetic linkage of urinary albumin excretion in Dahl salt-sensitive rats: influence of dietary salt and confirmation using congenic strains. , 2006, Physiological genomics.

[18]  R. Kreutz,et al.  A major gene locus links early onset albuminuria with renal interstitial fibrosis in the MWF rat with polygenetic albuminuria. , 2003, Journal of the American Society of Nephrology : JASN.

[19]  M. Garrett,et al.  Time-course genetic analysis of albuminuria in Dahl salt-sensitive rats on low-salt diet. , 2003, Journal of the American Society of Nephrology : JASN.

[20]  W. Hörl,et al.  Multifactorial Determination of Hypertensive Nephroangiosclerosis , 2003, Kidney and Blood Pressure Research.

[21]  R. Kreutz,et al.  Genetic dissection of increased urinary albumin excretion in the munich wistar frömter rat. , 2002, Journal of the American Society of Nephrology : JASN.

[22]  H. Jacob,et al.  Evidence of gene-gene interactions in the genetic susceptibility to renal impairment after unilateral nephrectomy. , 2000, Journal of the American Society of Nephrology : JASN.

[23]  T. Serikawa,et al.  A genetic locus susceptible to the overt proteinuria in BUF/Mna rat , 1998, Mammalian Genome.

[24]  D. Warnock,et al.  Kidney disease in the first-degree relatives of African-Americans with hypertensive end-stage renal disease. , 1996, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[25]  B. Freedman,et al.  Familial risk, age at onset, and cause of end-stage renal disease in white Americans. , 1995, Journal of the American Society of Nephrology : JASN.

[26]  B. Freedman,et al.  The familial risk of end-stage renal disease in African Americans. , 1993, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[27]  D. Ganten,et al.  Renal disease and the development of hypertension in salt-sensitive Dahl rats. , 1988, Kidney international.

[28]  C. Grim,et al.  A familial risk of chronic renal failure among blacks on dialysis? , 1988, Journal of clinical epidemiology.

[29]  Goldblatt Pj,et al.  Morphometric evaluation of the renal arterial system of Dahl salt-sensitive and salt-resistant rats on a high salt diet. I: Interlobar and arcuate arteries , 1987 .

[30]  L. Tassinari,et al.  EFFECTS OF CHRONIC EXCESS SALT INGESTION , 1962, The Journal of experimental medicine.

[31]  LEWIS K. DAHL,et al.  Role of Genetic Factors in Susceptibility to Experimental Hypertension due to Chronic Excess Salt Ingestion , 1962, Nature.

[32]  Ross Ward,et al.  United States Renal Data System , 2011 .

[33]  B. Kasiske,et al.  Excerpts from the United States Renal Data System 2007 annual data report. , 2008 .

[34]  L. Tassinari,et al.  GENETIC FACTORS IN HYPERTENSION FROM SALT FEEDING , 2003 .

[35]  E. Gruenstein,et al.  A simple, nonradioactive method for evaluating single-nephron filtration rate using FITC-inulin. , 1999, American journal of physiology. Renal physiology.

[36]  M. Daly,et al.  Renal disease susceptibility and hypertension are under independent genetic control in the fawn-hooded rat , 1996, Nature Genetics.

[37]  L. Duzzi,et al.  Relations between hypertension and glomerulosclerosis in first-generation hybrid rats of the Milan strains. , 1991, Child nephrology and urology.

[38]  M. Matsuyama,et al.  Genetic regulation of the development of glomerular sclerotic lesions in the BUF/Mna rat. , 1990, Nephron.

[39]  D. Lacher,et al.  Morphometric evaluation of the renal arterial system of Dahl salt-sensitive and salt-resistant rats on a high salt diet. II. Interlobular arteries and intralobular arterioles. , 1989, Laboratory investigation; a journal of technical methods and pathology.