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. AbstractIn 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.

Renal tissue hypoperfusion and hypoxia are early key elements in the pathophysiology of acute kidney injury of various origins, and may also promote progression from acute injury to chronic kidney disease. Here we describe test interventions that are used to study the control of renal hemodynamics and oxygenation in experimental animals in the context of kidney-specific control of hemodynamics and oxygenation. The rationale behind the use of the individual tests, the physiological responses of renal hemodynamics and oxygenation, the use in preclinical studies, and the possible application in humans are discussed.This chapter is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers.

Ischemia-reperfusion injury of the kidney is caused by the sudden and temporary obstruction of blood flow to the organ. Renal ischemia-reperfusion injury is associated with high morbidity and mortality, but effective therapies are lacking. Sexual dimorphism in renal injury has been acknowledged since the 1940s, and the possible role of sex hormones has been intensively investigated in the past decades. Clinical and experimental data demonstrate sexual differences in renal anatomy, physiology, and susceptibility to renal diseases including but not limited to ischemia-reperfusion injury. Some data suggest the protective role of female sex hormones, whereas others highlight the detrimental effect of male hormones in renal ischemia-reperfusion injury. Although the important role of sex hormones is evident, the exact underlying mechanisms remain to be elucidated. This review focuses on collecting the current knowledge about sexual dimorphism of renal ischemia-reperfusion injury, with emphasis on molecular mechanisms and potential novel therapeutic strategies.