The prepubertal years of type 1 diabetes (DM) appear to be protected from expression of nephropathy and other microvascular complications. Only post-pubertal male rats given the diabetogenic agent streptozocin (STZ) develop renal and glomerular hypertrophy associated with increased expression and activity of transforming growth factor b (TGFb). Prepubertal rats do not develop hypertrophy or upregulation of the TGF system. Given clinical differences in the prevalence and rate of progression between the sexes, gonadal steroids seem likely to be involved in these processes. Overall hypothesis: Androgen synthesis that accompanies puberty contributes to the development of diabetic nephropathy via changes in the renal transforming growth factor (TGF(3) system.
Specific Aims : I) What are the roles of androgens in diabetic kidney disease? 1)Examine sex differences in the renal reponse to STZ DM; 2)Examine the effects of gonadectomy on the post-pubertal renal response to STZ DM; 3)Determine the effect of testosterone treatment on the renal response to STZ DM; 4)Determine the role of the androgen receptor in the renal response to DM; and 5)Determine whether conversion to dihydrotestosterone is necessary for the post-pubertal renal response to STZ DM. II) What is the mechanism through which puberty promotes TGFfi expression/activation? 1 )Examine the renin-angiotensin system in response to pre- and post-pubertal states and hormonal manipulation; 2)Examine the protein kinase C system in response to pre- and post-pubertal states and hormonal manipulation; 3)Examine the oxidative stress system in response to pre- and post-pubertal states and hormonal manipulation; 4)Define the direct effects of sex steroids in vitro on the oxidative stress pathway; and 5)Define the direct effects of sex steroids in vitro on the PKC pathway. Methods: Rats will be given STZ DM pre- or post-puberty for 6 weeks, a duration of DM which increases TGFI3 expression and renal weight in adults. Groups will include males and females with and without earlier gonadectomy. Some groups will also receive treatment with testosterone, flutamide, an androgen receptor blocker, or finasteride, which blocks conversion of testosterone to dihydrotestosterone. in vitro studies will involve kidney slice cultures from 10 week old castrated male rats, with or without prior induction of OM. Media will include normal or high glucose conditions, as well as variable amounts of testosterone or estrogen. Measurements will include TGFJ3 proteins by ELISA and nitric oxide synthase isoforms, angiotensin II receptor, and protein kinase C isoforms by immunoblotting; superoxide generation; nitric oxide synthase activity; protein kinase C activity; mRNA for TGFb, nitric oxide synthases, and TGFb inducible gene-H3 by RT-PCR; plasma and renal levels of angiotensin II; and blood levels of sex steroids by RIA. Health implications: New treatments to prevent diabetic kidney disease, the most important cause of kidney failure in the US, may emerge from a better understanding of a naturally protected state such as the prepubertal animal.
| Lane, Pascale H (2005) Pediatric aspects of diabetic kidney disease. Adv Chronic Kidney Dis 12:230-5 |
| Lane, Pascale H (2002) Diabetic kidney disease: impact of puberty. Am J Physiol Renal Physiol 283:F589-600 |
