title: Chronic bilateral renal denervation attenuates renal injury in a transgenic rat model of diabetic nephropathy.
abstract: Bilateral renal denervation (BRD) has been shown to reduce hypertension and improve renal function in both human and experimental studies. We hypothesized that chronic intervention with BRD may also attenuate renal injury and fibrosis in diabetic nephropathy. This hypothesis was examined in a female streptozotocin-induced diabetic (mRen-2)27 rat (TGR) shown to capture the cardinal features of human diabetic nephropathy. Following diabetic induction, BRD/sham surgeries were conducted repeatedly (at the week 3, 6, and 9 following induction) in both diabetic and normoglycemic animals. Renal denervation resulted in a progressive decrease in systolic blood pressure from first denervation to termination (at 12 wk post-diabetic induction) in both normoglycemic and diabetic rats. Renal norepinephrine content was significantly raised following diabetic induction and ablated in denervated normoglycemic and diabetic groups. A significant increase in glomerular basement membrane thickening and mesangial expansion was seen in the diabetic kidneys; this morphological appearance was markedly reduced by BRD. Immunohistochemistry and protein densitometric analysis of diabetic innervated kidneys confirmed the presence of significantly increased levels of collagens I and IV, α-smooth muscle actin, the ANG II type 1 receptor, and transforming growth factor-β. Renal denervation significantly reduced protein expression of these fibrotic markers. Furthermore, BRD attenuated albuminuria and prevented the loss of glomerular podocin expression in these diabetic animals. In conclusion, BRD decreases systolic blood pressure and reduces the development of renal fibrosis, glomerulosclerosis, and albuminuria in this model of diabetic nephropathy. The evidence presented strongly suggests that renal denervation may serve as a therapeutic intervention to attenuate the progression of renal injury in diabetic nephropathy.
authors.affiliation: Department of Pharmacology, University of Otago, Dunedin, New Zealand; Australian School of Advanced Medicine, Macquarie University, New South Wales, Australia.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Department of Pharmacology, University of Otago, Dunedin, New Zealand;
authors.forename: Ingrid C
authors.initials: IC
authors.lastname: Fomison-Nurse
authors.affiliation: Department of Pharmacology, University of Otago, Dunedin, New Zealand;
authors.forename: Joanne C
authors.initials: JC
authors.lastname: Harrison
authors.affiliation: Department of Medicine, University of Otago, Dunedin, New Zealand;
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Walker
authors.affiliation: Department of Physiology, University of Otago, Dunedin, New Zealand; and.
authors.forename: Gerard
authors.initials: G
authors.lastname: Davis
authors.affiliation: Department of Pharmacology, University of Otago, Dunedin, New Zealand; ivan.sammut@otago.ac.nz.
authors.forename: Ivan A
authors.initials: IA
authors.lastname: Sammut
mesh_terms: D058186:Acute Kidney Injury / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D001485:Basement Membrane / Q000473:pathology; D003714:Denervation / Q000379:methods*; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications*; D003928:Diabetic Nephropathies / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005355:Fibrosis; D006579:Heterozygote; D007668:Kidney / Q000294:innervation*; D007678:Kidney Glomerulus / Q000473:pathology; D051381:Rats; D055647:Rats, Transgenic; D012083:Renin / Q000235:genetics* / Q000502:physiology; D013311:Streptozocin / Q000009:adverse effects
chemical_list: D013311:Streptozocin; D012083:Renin
keywords: (mRen-2)27 rat; diabetic nephropathy; fibrosis; renal denervation