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01-07-2010 | Original Article

Maternal diabetes programs hypertension and kidney injury in offspring

Authors: Yun-Wen Chen, Isabelle Chenier, Stella Tran, Michael Scotcher, Shiao-Ying Chang, Shao-Ling Zhang

Published in: Pediatric Nephrology | Issue 7/2010

Abstract

We investigated whether maternal diabetes programs the offspring to develop hypertension and kidney injury in adulthood and examined potential underlying mechanisms. In a murine model we studied the offspring of three groups of dams (non-diabetic, diabetic, and diabetic treated with insulin). Mean systolic blood pressure in the offspring was monitored from 8 to 20 weeks. Body and kidney weights in the offspring of diabetic mothers were significantly lower than in offspring of non-diabetic mothers. Offspring of diabetic mothers developed hypertension, microalbuminuria, and glucose intolerance. Increased accumulation of extracellular matrix proteins in the glomeruli and marked upregulation of angiotensinogen, angiotensin II type 1 receptor, angiotensin-converting enzyme, transforming growth factor beta-1 (TGF-β1), and plasminogen activator inhibitor-1 (PAI-1) gene expression were evident in the renal cortex of hypertensive offspring of diabetic mothers. By contrast, angiotensin-converting enzyme-2 (ACE2) gene expression was lower in the hypertensive offspring of diabetic mothers than in that of non-diabetic mothers. These changes were prevented in the offspring of insulin-treated diabetic mothers. These data indicate that maternal diabetes induces perinatal programming of hypertension, renal injury, and glucose intolerance in the offspring and suggest a central role for the activation of the intrarenal renin–angiotensin system and TGF-β1 gene expression in this process.

Aerts L, Van Assche FA (1977) Rat foetal endocrine pancreas in experimental diabetes. J Endocrinol 73:339–346CrossRefPubMed

Devaskar S, McMenamy K, Holtzclaw L, Sadiq F (1990) Long-term maternal-fetal exposure to high-low insulin concentrations alter liver but not brain insulin receptors. Am J Obstet Gynecol 163:1350–1356PubMed

Kervran A, Guillaume M, Jost A (1978) The endocrine pancreas of the fetus from diabetic pregnant rat. Diabetologia 15:387–393CrossRefPubMed

Do Carmo Pinho FM, Nigro D, Fortes ZB, Tostes RC, Carvalho MH, Lucas SR, Gomes GN, Coimbra TM, Gil FZ (2003) Intrauterine undernutrition—renal and vascular origin of hypertension. Cardiovasc Res 60:228–234CrossRef

Valdez R, Athens MA, Thompson GH, Bradshaw BS, Stern MP (1994) Birthweight and adult health outcomes in a biethnic population in the USA. Diabetologia 37:624–631CrossRefPubMed

Plagemann A (2006) Perinatal programming. J Perinat Med 34:256–257CrossRef

Luyckx VA, Brenner BM (2005) Low birth weight, nephron number, and kidney disease. Kidney Int Suppl (97):S68–S77

Ingelfinger JR (2004) Pathogenesis of perinatal programming. Curr Opin Nephrol Hypertens 13:459–464CrossRefPubMed

Ingelfinger JR, Woods LL (2002) Perinatal programming, renal development, and adult renal function. Am J Hypertens 15:46S–49SCrossRefPubMed

10.

Kucera J (1971) Rate and type of congenital anomalies among offspring of diabetic women. J Reprod Med 7:73–82PubMed

11.

Vohr BR, Boney CM (2008) Gestational diabetes: the forerunner for the development of maternal and childhood obesity and metabolic syndrome? J Matern Fetal Neonatal Med 21:149–157CrossRefPubMed

12.

Clausen TD, Mathiesen ER, Hansen T, Pedersen O, Jensen DM, Lauenborg J, Damm P (2008) High prevalence of type 2 diabetes and pre-diabetes in adult offspring of women with gestational diabetes mellitus or type 1 diabetes: the role of intrauterine hyperglycemia. Diabetes Care 31:340–346CrossRefPubMed

13.

Pettitt DJ, Lawrence JM, Beyer J, Hillier TA, Liese AD, Mayer-Davis B, Loots B, Imperatore G, Liu L, Dolan LM, Linder B, Dabelea D (2008) Association between maternal diabetes in utero and age at offspring’s diagnosis of type 2 diabetes. Diabetes Care 31:2126–2130CrossRefPubMed

14.

Hughson M, Farris AB III, Douglas-Denton R, Hoy WE, Bertram JF (2003) Glomerular number and size in autopsy kidneys: the relationship to birth weight. Kidney Int 63:2113–2122CrossRefPubMed

15.

Keller G, Zimmer G, Mall G, Ritz E, Amann K (2003) Nephron number in patients with primary hypertension. N Engl J Med 348:101–108CrossRefPubMed

16.

Manalich R, Reyes L, Herrera M, Melendi C, Fundora I (2000) Relationship between weight at birth and the number and size of renal glomeruli in humans: a histomorphometric study. Kidney Int 58:770–773CrossRefPubMed

17.

White SL, Perkovic V, Cass A, Chang CL, Poulter NR, Spector T, Haysom L, Craig JC, Salmi IA, Chadban SJ, Huxley RR (2009) Is low birth weight an antecedent of CKD in later life? A systematic review of observational studies. Am J Kidney Dis 54:248–261CrossRefPubMed

18.

Tran S, Chen YW, Chenier I, Chan JS, Quaggin S, Hebert MJ, Ingelfinger JR, Zhang SL (2008) Maternal diabetes modulates renal morphogenesis in offspring. J Am Soc Nephrol 19:943–952CrossRefPubMed

19.

Zhang SL, Chen YW, Tran S, Chenier I, Hebert MJ, Ingelfinger JR (2007) Reactive oxygen species in the presence of high glucose alter ureteric bud morphogenesis. J Am Soc Nephrol 18:2105–2115CrossRefPubMed

20.

Brezniceanu ML, Liu F, Wei CC, Chenier I, Godin N, Zhang SL, Filep JG, Ingelfinger JR, Chan JS (2008) Attenuation of interstitial fibrosis and tubular apoptosis in db/db transgenic mice overexpressing catalase in renal proximal tubular cells. Diabetes 57:451–459CrossRefPubMed

21.

Liu F, Brezniceanu ML, Wei CC, Chenier I, Sachetelli S, Zhang SL, Filep JG, Ingelfinger JR, Chan JS (2008) Overexpression of angiotensinogen increases tubular apoptosis in diabetes. J Am Soc Nephrol 19:269–280CrossRefPubMed

22.

Raizada V, Skipper B, Luo W, Griffith J (2007) Intracardiac and intrarenal angiotensin systems: mechanisms of cardiovascular and renal effects. J Investig Med 55:341–359CrossRefPubMed

23.

Kobori H, Nangaku M, Navar LG, Nishiyama A (2007) The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease. Pharmacol Rev 59:251–287CrossRefPubMed

24.

Brezniceanu ML, Liu F, Wei CC, Tran S, Sachetelli S, Zhang SL, Guo DF, Filep JG, Ingelfinger JR, Chan JS (2007) Catalase overexpression attenuates angiotensinogen expression and apoptosis in diabetic mice. Kidney Int 71:912–923CrossRefPubMed

25.

Liu F, Wei CC, Wu SJ, Chenier I, Zhang SL, Filep JG, Ingelfinger JR, Chan JS (2009) Apocynin attenuates tubular apoptosis and tubulointerstitial fibrosis in transgenic mice independent of hypertension. Kidney Int 75:156–166CrossRefPubMed

26.

Sachetelli S, Liu Q, Zhang SL, Liu F, Hsieh TJ, Brezniceanu ML, Guo DF, Filep JG, Ingelfinger JR, Sigmund CD, Hamet P, Chan JS (2006) RAS blockade decreases blood pressure and proteinuria in transgenic mice overexpressing rat angiotensinogen gene in the kidney. Kidney Int 69:1016–1023CrossRefPubMed

27.

Brezniceanu ML, Wei CC, Zhang SL, Hsieh TJ, Guo DF, Hebert MJ, Ingelfinger JR, Filep JG, Chan JS (2006) Transforming growth factor-beta 1 stimulates angiotensinogen gene expression in kidney proximal tubular cells. Kidney Int 69:1977–1985CrossRefPubMed

28.

Tolivia J, Navarro A, del Valle E, Perez C, Ordonez C, Martinez E (2006) Application of Photoshop and Scion Image analysis to quantification of signals in histochemistry, immunocytochemistry and hybridocytochemistry. Anal Quant Cytol Histol 28:43–53PubMed

29.

Weibel ER (1980) Numerical density: shape and size of particles. In: Weibel ER (ed) Sterological methods, vol 2. Theoretical foundations. Academic Press, London, pp 149–152

30.

Ferrario CM, Jessup J, Gallagher PE, Averill DB, Brosnihan KB, Ann TE, Smith RD, Chappell MC (2005) Effects of renin-angiotensin system blockade on renal angiotensin-(1-7) forming enzymes and receptors. Kidney Int 68:2189–2196CrossRefPubMed

31.

Ingelfinger JR (2009) Angiotensin-converting enzyme 2: implications for blood pressure and kidney disease. Curr Opin Nephrol Hypertens 18:79–84CrossRefPubMed

32.

Koka V, Huang XR, Chung AC, Wang W, Truong LD, Lan HY (2008) Angiotensin II up-regulates angiotensin I-converting enzyme (ACE), but down-regulates ACE2 via the AT1-ERK/p38 MAP kinase pathway. Am J Pathol 172:1174–1183CrossRefPubMed

33.

Huang Y, Noble NA (2007) PAI-1 as a target in kidney disease. Curr Drug Targets 8:1007–1015CrossRefPubMed

34.

Srinivasan M, Aalinkeel R, Song F, Patel MS (2003) Programming of islet functions in the progeny of hyperinsulinemic/obese rats. Diabetes 52:984–990CrossRefPubMed

35.

Srinivasan M, Aalinkeel R, Song F, Mitrani P, Pandya JD, Strutt B, Hill DJ, Patel MS (2006) Maternal hyperinsulinemia predisposes rat fetuses for hyperinsulinemia, and adult-onset obesity and maternal mild food restriction reverses this phenotype. Am J Physiol Endocrinol Metab 290:E129–E134CrossRefPubMed

36.

Barker DJ, Osmond C (1988) Low birth weight and hypertension. BMJ 297:134–135CrossRefPubMed

37.

Brenner BM, Garcia DL, Anderson S (1988) Glomeruli and blood pressure. Less of one, more the other? Am J Hypertens 1:335–347PubMed

38.

Hoy WE, Bertram JF, Denton RD, Zimanyi M, Samuel T, Hughson MD (2008) Nephron number, glomerular volume, renal disease and hypertension. Curr Opin Nephrol Hypertens 17:258–265CrossRefPubMed

39.

Hughson MD, Douglas-Denton R, Bertram JF, Hoy WE (2006) Hypertension, glomerular number, and birth weight in African Americans and white subjects in the southeastern United States. Kidney Int 69:671–678CrossRefPubMed

40.

Hughson MD, Samuel T, Hoy WE, Bertram JF (2007) Glomerular volume and clinicopathologic features related to disease severity in renal biopsies of African Americans and whites in the southeastern United States. Arch Pathol Lab Med 131:1665–1672PubMed

41.

Hughson MD, Gobe GC, Hoy WE, Manning RD Jr, Douglas-Denton R, Bertram JF (2008) Associations of glomerular number and birth weight with clinicopathological features of African Americans and whites. Am J Kidney Dis 52:18–28CrossRefPubMed

42.

McNamara BJ, Diouf B, Hughson MD, Douglas-Denton RN, Hoy WE, Bertram JF (2008) Renal pathology, glomerular number and volume in a West African urban community. Nephrol Dial Transplant 23:2576–2585CrossRefPubMed

43.

Magaton A, Gil FZ, Casarini DE, Cavanal MF, Gomes GN (2007) Maternal diabetes mellitus—early consequences for the offspring. Pediatr Nephrol 22:37–43CrossRefPubMed

44.

Nehiri T, Duong Van Huyen JP, Viltard M, Fassot C, Heudes D, Freund N, Deschenes G, Houillier P, Bruneval P, Lelievre-Pegorier M (2008) Exposure to maternal diabetes induces salt-sensitive hypertension and impairs renal function in adult rat offspring. Diabetes 57:2167–2175CrossRefPubMed

45.

Border WA, Noble NA (1998) Interactions of transforming growth factor-beta and angiotensin II in renal fibrosis. Hypertension 31:181–188PubMed

46.

Kagami S, Kuhara T, Okada K, Kuroda Y, Border WA, Noble NA (1997) Dual effects of angiotensin II on the plasminogen/plasmin system in rat mesangial cells. Kidney Int 51:664–671CrossRefPubMed

Title: Maternal diabetes programs hypertension and kidney injury in offspring
Authors: Yun-Wen Chen
Isabelle Chenier
Stella Tran
Michael Scotcher
Shiao-Ying Chang
Shao-Ling Zhang
Publication date: 01-07-2010
Publisher: Springer-Verlag
Published in: Pediatric Nephrology / Issue 7/2010
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-010-1506-1

At a glance: The STEP trials

Springer Medicine

Maternal diabetes programs hypertension and kidney injury in offspring

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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