Transgenic overexpression of brain natriuretic peptide prevents the progression of diabetic nephropathy in mice

Abstract

Aims/hypothesis Brain natriuretic peptide (BNP) is a potent vasorelaxing and natriuretic peptide that is secreted from the heart and has cardioprotective properties. We have previously generated hypotensive transgenic mice (BNP-Tg mice) that overproduce BNP in the liver, which is released into the circulation. Using this animal model, we successfully demonstrated the amelioration of renal injury after renal ablation and in proliferative glomerulonephritis. Glomerular hyperfiltration is an early haemodynamic derangement, representing one of the key mechanisms of the pathogenesis of diabetic nephropathy. Based on the suggested involvement of increased endogenous natriuretic peptides, the aim of this study was to investigate their role in the development and progression of diabetic nephropathy. Materials and methods We evaluated the progression of renal injury and fibrogenesis in BNP-Tg mice with diabetes induced by streptozotocin. We also investigated the effect of BNP on high glucose-induced signalling abnormalities in mesangial cells. Results After induction of diabetes, control mice exhibited progressively increased urinary albumin excretion with impaired renal function, whereas these changes were significantly ameliorated in BNP-Tg mice. Notably, diabetic BNP-Tg mice revealed minimal mesangial fibrogenesis with virtually no glomerular hypertrophy. Glomerular upregulation of extracellular signal-regulated kinase, TGF-β and extracellular matrix proteins was also significantly inhibited in diabetic BNP-Tg mice. In cultured mesangial cells, activation of the above cascade under high glucose was abrogated by the addition of BNP. Conclusions/interpretation Chronic excess of BNP prevents glomerular injury in the setting of diabetes, suggesting that renoprotective effects of natriuretic peptides may be therapeutically applicable in preventing the progression of diabetic nephropathy.

Natriuretic Peptide Receptor Guanylyl Cyclase-A Protects Podocytes from Aldosterone-Induced Glomerular Injury

“…23 We previously showed that chronic excess of BNP in mice prevents glomerular injury after subtotal nephrectomy, 24 and ameliorates proteinuria and histologic changes in immune-mediated renal injury 25 as well as in diabetic nephropathy. 26 In addition to exerting direct vasodilating and diuretic actions, natriuretic peptides act to antagonize the RAAS at multiple steps. 14,27,28 We postulate therefore that the beneficial effects of natriuretic peptides should be brought about, at least in part, by antagonizing local activation and/or action of the RAAS in the kidney.…”

“…14,27,28 We postulate therefore that the beneficial effects of natriuretic peptides should be brought about, at least in part, by antagonizing local activation and/or action of the RAAS in the kidney. [24][25][26] To explore the role of natriuretic peptide/GC-A signaling in aldosterone-induced renal injury, we investigated renal findings of mice deficient in GC-A, along with the challenge of aldosterone and a high-salt diet.…”

Peritonitis-induced peritoneal injury models for research in peritoneal dialysis review of infectious and non-infectious models

“…ANP has been shown to play an important function in the inhibition of RAAS [44,45]. ANP and brain natriuretic peptide (BNP) have been reported to prevent cardiac fibrosis [44,46] and renal fibrosis [47][48][49], and to reduce infarct size in acute myocardial infarction [50]. We demonstrated that AT1R, ACE, and atrial natriuretic peptide receptor (NPR-A) mRNA expression were increased and peaked at days 14, 7, and 7, respectively.…”

Distinct roles for renal particulate and soluble guanylyl cyclases in preserving renal function in experimental acute heart failure

“…We demonstrated that endogenous ANP, which was activated shortly within 45 min after rapid ventricular pacing, may be important in the control of GFR and renal sodium excretion in experimental AHF. It is relevant to state that recent studies of chronic overexpression of BNP in a murine model of diabetic glomerulopathy resulted in a preservation of glomerular structure and function (28). As a therapeutic strategy for AHF, ANP administration or agents that potentiate the effect of ANP may have renal therapeutic potential in AHF.…”