2008 JASN IMPACT FACTOR 7.505	HOME   AUTHOR INFO   EDITORIAL BOARD   SUBSCRIBE   FEEDBACK   ALERTS   HELP
advanced	CURRENT ISSUE	ARCHIVES	JASN Express	ONLINE SUBMISSION

This Article Full Text (PDF) All Versions of this Article: ASN.2008010040v1 19/3/420    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Brown, R. W. Search for Related Content PubMed PubMed Citation Articles by Brown, R. W. Related Collections Related Article

Naturally Too Sympathetic to a Bad Diet?

Centre for Cardiovascular Science, Queen's Medical Research Institute, Edinburgh, United Kingdom

Correspondence: Dr. Roger Brown, Centre for Cardiovascular Science, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK. Phone: +44-131-2426739; Fax: +44-131-2426779; E-mail: roger.brown{at}ed.ac.uk

	Introduction

Top Introduction DISCLOSURES REFERENCES

 
An ominous upward trend in obesity, diabetes, and associated hypertension and their consequences warns all of us of a burden in cardiovascular disease already well developed in the United States and sweeping across Europe, many parts of Asia, and beyond. It seems set to get worse. This epidemic includes an alarming rise in chronic renal failure reaching ESRD and requiring long-term dialysis or transplantation. In the United States, this rose from approximately 42,000 in 1978 to >484,000 by 2005 (11.5-fold).¹ Black individuals of ancestral African descent are disproportionately susceptible to renal damage developing in this epidemic having particularly high rates of ESRD associated with hypertension. Reported prevalence rate of ESRD in black individuals is >2.5-fold the US population average.¹

Within this population are clear genetic factors causing susceptibility. In a small minority (8%) these are single-gene disorders, such as FSGS from mutations in genes encoding ACTN4, TRPC6, or CD2AP (FSGS1 through 3), and give insight into how susceptibility develops.² However the majority seem cases of a complex polygenic disorder: arising as ancestral genotypes, adapted to hunter-gatherer sub-Saharan lifestyle, interact with the modern, increasingly Westernized environment and a sedentary lifestyle. Diet has loomed large among environmental culprits. Presuming ancestral diets were low calorie and low sodium, selection would favor genotypes enabling increasing food intake and putting on weight when calories are available and retaining salt avidly, suiting a low-salt diet. On exposure to this Westernized lifestyle, these survival traits then predispose to obesity, diabetes, and hypertension. ESRD seems to be a particular vulnerability with nondiabetic ESRD usually attributed to hypertensive nephrosclerosis.

Understanding this genetic susceptibility of black individuals to ESRD is of great interest, and many candidate genes have been proposed and investigated, especially in pathways relating to renal damage or other renal structural diseases, such as TRPC6 (FSGS-2) or podocin (steroid-resistant nephrotic syndrome).³ Increasingly in this postgenomic, post-HapMap era, the rigor of candidate gene reports warrants serious consideration. In this issue of JASN, Salem et al.⁴ report that variations in chromogranin A (CHGA) genotype are associated with ESRD in hypertensive black individuals versus control subjects with normal renal function and hypertension or normotension. Multiple single-nucleotide polymorphisms (SNP) analyzed in a Californian cohort across the CHGA locus identify significant associations with a three-SNP proximal promoter haplotype and a 3'end/3'untranslated region two-SNP haplotype.

Importantly, findings in a second, unrelated cohort of black individuals from North Carolina validated significant associations of ESRD with both haplotypes (both emerging as two-SNP haplotypes). In both haplotype regions variation has potential to alter CHGA expression^4,5 with the 3'haplotype 87T SNP allele reducing expression in vitro by >40%.⁴ Consistent with such haplotype effects to lower gene transcription, circulating levels of catestatin (a chromogranin A cleavage product) were significantly reduced in patients with ESRD versus control subjects despite the tendency for accumulation in ESRD. Because catestatin is active in limiting catecholamine release, these findings suggest the ESRD-associated haplotypes would leave the sympathetic nervous system (SNS) less restrained, implying that relative SNS overactivity is pathophysiologically involved in the susceptibility to renal decline.

Could catecholamine release and sympathetic overactivity really be key processes underpinning hypertensive renal damage and ESRD in black individuals? The suggestion certainly has potential to arouse skepticism. Although antihypertensive drug classes in use decades ago included a group limiting SNS activity (ganglion blockers, adrenergic 2 agonists [e.g., clonidine], -methyl DOPA, and β blockers), it was not these but diuretics that emerged as particularly valuable in treating hypertension and its consequences in black individuals.

Such hypertension is indeed salt sensitive, and guidance favoring diuretics remains in many current guidelines on treatment of hypertension.^6,7 However it is important to appreciate that the association with chromogranin A is not with hypertension but renal damage, potentially largely independent of systemic hypertension. Indeed, in the important African American Study of Kidney Disease and Hypertension (AASK), factors other than systemic BP (mainly proteinuria) and drugs other than diuretics emerged as key in limiting decline in renal function.⁸

That angiotensin-converting enzyme inhibitors (ACEi) were best and β blockers probably worst at limiting renal damage also seems to give little support to the role of sympathetic overactivity in these processes. However, dysregulation of glomerular hemodynamics leading to glomerular hypertension-driven proteinuria seem to be involved and ameliorated by ACEi. It is possible that the wrong balance of and β adrenergic overactivity could promote dysregulation of glomerular hemodynamics and not be optimally resolved by β blockade. Blockers certainly can alter glomerular pressure, and studies showing combined and β blockade ameliorating renal damage and proteinuria in animals are known.⁹ More intriguing still, there are 6 adrenoceptors (fully selective blockers are not available), and, in mice, null alleles of 1a¹⁰ or 1d¹¹ lower and 2a¹² raise BP, and these along with 2b¹³ are implicated in separate chronic salt-sensitive SNS responses and BP abnormalities.

Because high-salt intake, obesity, and uremia all are associated with SNS overactivity, it is clear that abnormalities in selective adrenoceptor pathways might be a route through which sympathetic overactivity promotes salt-sensitive hypertension and simultaneous vulnerability to renal damage. Finally, chromogranin A haplotypes (and perhaps reduced circulating catestatin) are potentially valuable markers in identifying a subset of people who may benefit from specific treatment to avoid ESRD (for example, ACEi) at an early stage: rather like impaired glucose tolerance (another marker of the Western-lifestyle epidemic), warrants assessment of need for such treatment.

This report⁴ is rigorous in validating initial haplotype findings in a second population, although the studies presented nonetheless have weaknesses (e.g., sympathetic tone changes with age and control subjects are an average 10 yr younger). It seems that further study is warranted for both this interesting candidate gene and the theory that sympathetic overactivity is an underestimated contributor to ESRD.

Although considerable further evidence would need to follow to verify the putative causal chain, ideally early developments would be that others would reproduce the findings in larger populations, and longitudinal studies in patient groups or animal models would demonstrate that sympathetic overactivity (and lower catestatin) precedes progressive decline to renal failure. Eventually, then, the value of these CHGA haplotypes and catestatin as markers and perhaps the benefits of medication that is capable of limiting the distorted sympathetic outflow, perhaps limiting certain adrenergic effects, might then be worth assessment in those who are at high risk for ESRD.

	DISCLOSURES

Top Introduction DISCLOSURES REFERENCES

 
None.

	Footnotes

 
Published online ahead of print. Publication date available at www.jasn.org.

See related article, "Chromogranin A Polymorphisms Are Associated with Hypertensive Renal Disease," on pages 600–614.

	REFERENCES

Top Introduction DISCLOSURES REFERENCES

 

1. US Renal Data System: USRDS 2007 Annual Data Report, Bethesda, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2007 . Available at: http://www.usrds.org/adr.htm. Accessed January 5, 2008
2. Schelling JR, Zarif L, Sehgal A, Iyengar S, Sedor JR: Genetic susceptibility to end-stage renal disease. Curr Opin Nephrol Hypertens 8 : 465 –472, 1999[CrossRef][Medline]
3. Dusel JA, Burdon KP, Hicks PJ, Hawkins GA, Bowden DW, Freedman BI: Identification of podocin (NPHS2) gene mutations in African Americans with nondiabetic end-stage renal disease. Kidney Int 68 : 256 –262, 2005[CrossRef][Medline]
4. Salem RM, Cadman PE, Chen Y, Rao F, Wen G, Hamilton BA, Rana BK, Smith DW, Stridsberg M, Ward HJ, Bowden DW, Hicks PJ, Freedman BI, Schork NJ, O'Connor DT: Chromogranin A polymorphisms are associated with hypertensive renal disease. J Am Soc Nephrol 19 : 600 –614, 2008[Abstract/Free Full Text]
5. Wen G, Mahata SK, Cadman P, Mahata M, Ghosh S, Mahapatra NR, Rao F, Stridsberg M, Smith DW, Mahboubi P, Schork NJ, O'Connor DT, Hamilton BA: Both rare and common polymorphisms contribute functional variation at CHGA, a regulator of catecholamine physiology. Am J Hum Genet 74 : 197 –207, 2004[CrossRef][Medline]
6. Williams B, Poulter NR, Brown MJ, Davis M, McInnes GT, Potter JF, Sever PS, McG Thom S, for the British Hypertension Society: Guidelines for management of hypertension: report of the fourth working party of the British Hypertension Society, 2004-BHS IV. J Hum Hypertens 18 : 139 –185, 2004[CrossRef][Medline]
7. World Health Organization: Prevention of Cardiovascular Disease: Guidelines for Assessment and Management of Cardiovascular Risk, Geneva, Switzerland: WHO Press, World Health Organization. Available at: http://www.who.int/cardiovascular_diseases/guidelines/Prevention_of_Cardiovascular_Disease/en. Accessed January 5, 2008
8. Toto RD: Lessons from the African-American Study of Kidney Disease and Hypertension: An update. Curr Hypertens Rep 8 : 409 –412, 2006[CrossRef][Medline]
9. Amann K, Koch A, Hofstetter J, Gross ML, Haas C, Orth SR, Ehmke H, Rump LC, Ritz E: Glomerulosclerosis and progression: Effect of sub-antihypertensive doses of alpha and beta blockers. Kidney Int 60 : 1309 –1323, 2001[CrossRef][Medline]
10. Rokosh DG, Simpson PC: Knockout of the alpha 1A/C-adrenergic receptor subtype: The alpha 1A/C is expressed in resistance arteries and is required to maintain arterial blood pressure. Proc Natl Acad Sci U S A 99 : 9474 –9479, 2002[Abstract/Free Full Text]
11. Tanoue A, Nasa Y, Koshimizu T, Shinoura H, Oshikawa S, Kawai T, Sunada S, Takeo S, Tsujimoto G: The alpha(1D)-adrenergic receptor directly regulates arterial blood pressure via vasoconstriction. J Clin Invest 109 : 765 –775, 2002[CrossRef][Medline]
12. Hein L, Altman JD, Kobilka BK: Two functionally distinct alpha2-adrenergic receptors regulate sympathetic neurotransmission. Nature 402 : 181 –184, 1999[CrossRef][Medline]
13. Makaritsis KP, Handy DE, Johns C, Kobilka B, Gavras I, Gavras H: Role of the alpha2B adrenergic receptor in the development of salt-induced hypertension. Hypertension 33 : 14 –17, 1999[Abstract/Free Full Text]

This Article Full Text (PDF) All Versions of this Article: ASN.2008010040v1 19/3/420    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Brown, R. W. Search for Related Content PubMed PubMed Citation Articles by Brown, R. W. Related Collections Related Article