Pediatr Nephrol (2005) 20:858–866 DOI 10.1007/s00467-005-1888-7 INVITED REVIEW Yashpal S. Kanwar · Baibaswata Nayak · Sun Lin · Shigeru Akagi · Ping Xie · Jun Wada · Sumant S. Chugh · Farhad R. Danesh Hyperglycemia: its imminent effects on mammalian nephrogenesis Received: 25 May 2004 / Revised: 26 January 2005 / Accepted: 31 January 2005 / Published online: 5 May 2005  IPNA 2005 Abstract A sustained exposure of the mammalian em- bryo to very high glucose ambience is associated with a multitude of congenital birth defects, including those of the cardiovascular, CNS, skeletal and urogenital systems during the first 6–8 weeks of gestation in humans. These urogenital abnormalities may be associated with “caudal regression syndrome” or may occur alone in the form of partial or total renal agenesis. Similarly, an increase in the incidence of morphogenetic defects is observed in the offspring of streptozotocin-induced diabetic rats and mice, and also in non-obese diabetic mice. In certain cases, failure during the growth of the lower parts of embryos or newborn mice involving the genitourinary system has been observed in animals with severe diabetes. Investigators have utilized whole organ culture systems to delineate the mechanisms relevant to dysmorphogenesis of the embryonic metanephros. A marked dysmorpho- genesis of the metanephros is observed upon treatment with a high concentration of d-glucose. Associated with it are changes that include branching dysmorphogenesis of the ureteric bud iterations, reduced population of nascent nephrons, decreased expression of basement membrane proteoglycans, depletion of ATP stores, and fulminant apoptosis of the cells at the interface of mesenchyme and ureteric bud epithelium. The latter findings suggest that disruption of epithelial:mesenchymal interactions may be the major event responsible for the metanephric dys- morphogenesis induced by high glucose ambience. Keywords Diabetic nephropathy · Renal development · Dysmorphogenesis · High glucose · Hyperglycemia Introduction Hyperglycemia in man and other mammals is regarded as one of the characteristic signs of the onset of a complex metabolic disorder referred to as diabetes mellitus. Met- abolic derangements associated with diabetes lead to a wide range of acute reversible and chronic cumulative irreversible damage in several organ systems, including to the blood vessels, nerves, muscles, eyes and kidneys [1, 2]. Acute metabolic changes may be due to the pertur- bations in myoinositol and diacylglycerol levels, activa- tion of protein kinase C, glycation of proteins and gen- eration of oxygen free radicals that ultimately inflict damage to a wide variety of tissues. In addition, increased activity in the polyol pathway leads to excessive gener- ation of sorbitol, which in turn induces osmotic stress. The chronic changes are insidious and are targeted to- wards molecules with a relatively slow metabolic turn- over, such as DNA, eye lens protein and collagen. One of these chronic changes is non-enzymatic glycation of ex- tracellular matrix (ECM) protein, such as collagen, that apparently results in part due to the generation of ad- vanced glycation end-products (AGEs). The AGEs can induce oxidant stress, while the glycated ECM proteins undergo abnormal cross-linking with one another with excessive accumulation and disordered organization of the ubiquitously-distributed basement membranes causing expected widespread damage in diabetes mellitus in adult life [3]. This may also be the case during embryonic life, where the fetus is exposed to sustained high glucose ambience and the damage may be widespread, affecting multiple organs, which is collectively referred to as dia- betic embryopathy [4]. The syndrome includes malfor- mations confined to central nervous system (CNS), and Y. S. Kanwar ( ) ) · B. Nayak · S. Lin · S. Akagi · P. Xie Department of Pathology, Northwestern University Medical School, Chicago, IL, USA e-mail: y-kanwar@northwestern.edu Tel.: +1-312-5030084 Fax: +1-312-503-0627 Y. S. Kanwar · S. S. Chugh · F. R. Danesh Department of Medicine, Northwestern University Medical School, Chicago, IL, USA J. Wada Department of Medicine, Okayama University, Okayama, Japan