Abstract
BackgroundHuman and animal studies support the idea that there are sex differences in the development of diabetic renal disease. Our lab and others have determined that in addition to Ang II (through the AT1R), growth hormone (GH) contributes to renal damage in models of renal failure; however, the impact of sex and GH on the mechanisms initiating diabetic renal disease is not known. This study examined the effect of sex and GH on parameters of renal damage in early, uncontrolled streptozotocin (STZ)-induced diabetes.MethodsAdult male and female Sprague–Dawley rats were injected with vehicle (control), STZ, or STZ + GH and euthanized after 8 weeks.ResultsMild but significant glomerulosclerosis (GS) and tubulointerstitial fibrosis (TIF) was observed in both kidneys from male and female diabetic rats, with GH significantly increasing GS and TIF by 30% and 25% in male rats, but not in female rats. STZ increased TGF-β expression in both kidneys from male and female rats; however, while GH had no further effect on TGF-β protein in diabetic females, GH increased TGF-β protein in the male rat’s kidneys by an additional 30%. This sex-specific increase in renal injury following GH treatment was marked by increased MCP-1 and CD-68+ cell density. STZ also reduced renal MMP-2 and MMP-9 protein expression in both kidneys from male and female rats, but additional decreases were only observed in GH-treated diabetic male rats. The sex differences were independent of AT1R activity.ConclusionsThese studies indicate that GH affects renal injury in diabetes in a sex-specific manner and is associated with an increase in pro-inflammatory mediators.
Highlights
Human and animal studies support the idea that there are sex differences in the development of diabetic renal disease
There was no additional effect of growth hormone (GH) on blood glucose nor were there sex differences seen in blood glucose within treatment groups, with the limitation that all STZ groups were shown with blood glucose above 400 mg/dl
While previous studies have highlighted the issues of sex differences and GH effects in diabetic renal disease separately, the present work shows sex-related differences in response to GH in diabetic renal disease
Summary
Human and animal studies support the idea that there are sex differences in the development of diabetic renal disease. This study examined the effect of sex and GH on parameters of renal damage in early, uncontrolled streptozotocin (STZ)-induced diabetes. Growth hormone (GH) has been shown to exacerbate progression of kidney damage in a number of experimental models of renal disease [1,2,3,4], including diabetes [5]. Suppression of plasma GH by STZ is observed in female rats (unpublished data from this laboratory) This decrease seen in GH levels is opposite of what is seen in patients with type 1 diabetes, where GH levels are dysregulated, and usually elevated compared to nondiabetic control patients [8,12]. We hypothesize that the loss of GH in the STZ model impacts the development of diabetic kidney disease and that using an STZ model with GH supplementation will more accurately reflect the human condition
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