RAAS inhibitors directly reduce diabetes‐induced renal fibrosis via growth factor inhibition

Autor: Ádám Vannay, Attila J. Szabo, Agnes Molnar, László Wagner, Lilla Lenart, Federica Genovese, Edgar Szkibinszkij, Dora Balogh, Adam Hosszu, Sandor Koszegi, Andrea Fekete, Judit Hodrea, Nadja Sparding, Tamas Lakat
Rok vydání: 2018
Předmět:
Male
0301 basic medicine
Physiology
medicine.medical_treatment
Angiotensin-Converting Enzyme Inhibitors
Growth Factor Inhibition
Spironolactone
Kidney
Renin-Angiotensin System
0302 clinical medicine
Ramipril
Fibrosis
Diabetic Nephropathies
Mannitol
tubulointerstitial fibrosis
Renal
Mineralocorticoid Receptor Antagonists
biology
Proto-Oncogene Proteins c-sis
PDGF
Eplerenone
renin-angiotensin-aldosterone system inhibitors
renin‐angiotensin‐aldosterone system inhibitors
profibrotic growth factors
Platelet-derived growth factor receptor
Research Paper
medicine.drug
medicine.medical_specialty
Losartan
Cell Line
Diabetes Mellitus
Experimental
03 medical and health sciences
Internal medicine
medicine
Renal fibrosis
Animals
Humans
Rats
Wistar
business.industry
diabetic nephropathy
Growth factor
Connective Tissue Growth Factor
CTGF
Epithelial Cells
Fibroblasts
medicine.disease
030104 developmental biology
Endocrinology
biology.protein
Tubulointerstitial fibrosis
business
Angiotensin II Type 1 Receptor Blockers
030217 neurology & neurosurgery
Zdroj: The Journal of Physiology
Koszegi, S, Molnar, A, Lenart, L, Hodrea, J, Balogh, D B, Lakat, T, Szkibinszkij, E, Hosszu, A, Sparding, N, Genovese, F, Wagner, L, Vannay, A, Szabo, A J & Fekete, A 2019, ' RAAS inhibitors directly reduce diabetes-induced renal fibrosis via growth factor inhibition ', The Journal of Physiology, vol. 597, no. 1, pp. 193-209 . https://doi.org/10.1113/JP277002
ISSN: 1469-7793
0022-3751
Popis: Key points Increased activation of the renin‐angiotensin‐aldosterone system (RAAS) and elevated growth factor production are of crucial importance in the development of renal fibrosis leading to diabetic kidney disease.The aim of this study was to provide evidence for the antifibrotic potential of RAAS inhibitor (RAASi) treatment and to explore the exact mechanism of this protective effect.We found that RAASi ameliorate diabetes‐induced renal interstitial fibrosis and decrease profibrotic growth factor production.RAASi prevents fibrosis by acting directly on proximal tubular cells, and inhibits hyperglycaemia‐induced growth factor production and thereby fibroblast activation.These results suggest a novel therapeutic indication and potential of RAASi in the treatment of renal fibrosis. Abstract In diabetic kidney disease (DKD) increased activation of renin‐angiotensin‐aldosterone system (RAAS) contributes to renal fibrosis. Although RAAS inhibitors (RAASi) are the gold standard therapy in DKD, the mechanism of their antifibrotic effect is not yet clarified. Here we tested the antifibrotic and renoprotective action of RAASi in a rat model of streptozotocin‐induced DKD. In vitro studies on proximal tubular cells and renal fibroblasts were also performed to further clarify the signal transduction pathways that are directly altered by hyperglycaemia. After 5 weeks of diabetes, male Wistar rats were treated for two more weeks per os with the RAASi ramipril, losartan, spironolactone or eplerenone. Proximal tubular cells were cultured in normal or high glucose (HG) medium and treated with RAASi. Platelet‐derived growth factor (PDGF) or connective tissue growth factor (CTGF/CCN2)‐induced renal fibroblasts were also treated with various RAASi. In diabetic rats, reduced renal function and interstitial fibrosis were ameliorated and elevated renal profibrotic factors (TGFβ1, PDGF, CTGF/CCN2, MMP2, TIMP1) and alpha‐smooth muscle actin (αSMA) levels were decreased by RAASi. HG increased growth factor production of HK‐2 cells, which in turn induced activation and αSMA production of fibroblasts. RAASi decreased tubular PDGF and CTGF expression and reduced production of extracellular matrix (ECM) components in fibroblasts. In proximal tubular cells, hyperglycaemia‐induced growth factor production increased renal fibroblast transformation, contributing to the development of fibrosis. RAASi, even in non‐antihypertensive doses, decreased the production of profibrotic factors and directly prevented fibroblast activation. All these findings suggest a novel therapeutic role for RAASi in the treatment of renal fibrosis.
Key points Increased activation of the renin‐angiotensin‐aldosterone system (RAAS) and elevated growth factor production are of crucial importance in the development of renal fibrosis leading to diabetic kidney disease.The aim of this study was to provide evidence for the antifibrotic potential of RAAS inhibitor (RAASi) treatment and to explore the exact mechanism of this protective effect.We found that RAASi ameliorate diabetes‐induced renal interstitial fibrosis and decrease profibrotic growth factor production.RAASi prevents fibrosis by acting directly on proximal tubular cells, and inhibits hyperglycaemia‐induced growth factor production and thereby fibroblast activation.These results suggest a novel therapeutic indication and potential of RAASi in the treatment of renal fibrosis.
Databáze: OpenAIRE
Externí odkaz: