REVIEW Hypertension and kidneys: unraveling complex molecular mechanisms underlying hypertensive renal damage S Mennuni 1 , S Rubattu 1,2 , G Pierelli 1 , G Tocci 2 , C Fofi 3 and M Volpe 1,2 Kidney damage represents a frequent event in the course of hypertension, ranging from a benign to a malignant form of nephropathy depending on several factors, that is, individual susceptibility, degree of hypertension, type of etiology and underlying kidney disease. Multiple mechanisms are involved in determination of kidney glomerular, tubular and interstitial injuries in hypertension. The present review article discusses relevant contributory molecular mechanisms underpinning the promotion of hypertensive renal damage, such as the renin–angiotensin–aldosterone system (RAAS), oxidative stress, endothelial dysfunction, and genetic and epigenetic determinants. We highlighted major pathways involved in the progression of inflammation and fibrosis leading to glomerular sclerosis, tubular atrophy and interstitial fibrosis, thus providing a state of the art review of the pathogenetic background useful for a better understanding of current and future therapeutic strategies toward hypertensive nephropathy. An adequate control of high blood pressure, obtained through an appropriate therapeutic intervention, still represents the key strategy to achieve a satisfactory control of renal damage in hypertension. In this regard, we reviewed the impact of currently available antihypertensive pharmacological treatment on kidney damage, with particular regard to RAAS inhibitors. Notably, recent findings underscored the ability of the kidneys to regenerate and to repair tissue injuries through the differentiation of resident embryonic stem cells. Pharmacological modulation of the renal endogenous reparative process (that is, with angiotensin-converting enzyme inhibitors and AT1 angiotensin II receptor blockers), as well as future therapeutic strategies targeted to the renopoietic system, offers interesting perspectives for the management of hypertensive nephropathy. Journal of Human Hypertension advance online publication, 27 June 2013; doi:10.1038/jhh.2013.55 Keywords: hypertension; kidney damage; oxidative stress; renin–angiotensin system; inflammation; genetics INTRODUCTION The association between hypertension and renal disease is a well-known condition. Although the relative risk of serious renal damage in patients with uncomplicated essential hypertension is low, as compared with other cardiovascular complications, hypertension still remains owing to its huge prevalence in the general population, the second leading cause of end-stage renal disease (ESRD) after diabetes. 1 Patients with pre-existing renal disease and/or diabetes exhibit a greatly enhanced susceptibility to accelerated renal damage even with mild-to-moderate hypertension. 2 Moreover, subtle target organ damage, such as microalbuminuria, left ventricular hypertrophy and cognitive dysfunction, takes place early in the course of hypertension and can be left unrecognized until major complications occur. Historically, renal damage induced by hypertension has been separated into two distinct clinical and histological patterns of ‘benign’ and ‘malignant’ nephrosclerosis. In the context of hypertension, the development of chronic kidney disease (CKD) has to be considered as a cause of worsening prognosis due to cardiovascular adverse events and death. 2 However, CKD may not progress to its end-stage in all hypertensive patients, as many of them would eventually die for other hypertension-dependent cardiovascular diseases. In the present work, we aimed at providing a state of the art review of relevant molecular mechanisms involved in the pathogenesis of hypertensive nephropathy as a useful tool for both basic and clinical readership, and for a better understanding of current and future therapeutic strategies. The impact of current therapeutic interventions for the control of hypertensive nephropathy, such as the renin–angiotensin– aldosterone system (RAAS) inhibitors, is also discussed with regard to novel implications on the endogenous renopoietic reparative system. MATERIALS AND METHODS Literature search methodology Potentially eligible articles, available until December 2012 on electronic database (PubMed), and related references were used for our literature search. Search strategies were designed to identify articles that reported renal damage in hypertensive disease. In particular, we searched MEDLINE using multiple terms and combinations starting with ‘Hypertension and kidney’. Subsequently, we used the following as keywords: renal damage, hypertension, CKD, glomerulosclerosis, RAAS, oxidative stress, inflamma- tion, fibrosis, endothelial dysfunction, genetics and epigenetic determi- nants, and renopoietic system. The search identified 470 articles from 1977 to 2013, 200 of them provided relevant data on hypertensive renal damage and its mechanisms. When multiple articles were published on the same topic, the articles with the most complete set of data were considered. Some articles were excluded because there were no original available data, no mechanisms of renal damage and low quality analysis or evidence. 1 Department of Clinical and Molecular Medicine, School of Medicine and Psychology, University Sapienza of Rome, Ospedale S. Andrea, Rome, Italy; 2 IRCCS Neuromed, Pozzilli, Italy and 3 Nephrology and Dialysis Unit, School of Medicine and Psychology, University Sapienza of Rome, Ospedale S. Andrea, Rome, Italy. Correspondence: Professor S Rubattu or Professor M Volpe, Department of Clinical and Molecular Medicine, School of Medicine and Psychology, University Sapienza of Rome, Ospedale S. Andrea, Via di Grottarossa 1039, Rome, Italy. E-mail: rubattu.speranza@neuromed.it or massimo.volpe@uniroma1.it Received 5 February 2013; revised 12 April 2013; accepted 28 May 2013 Journal of Human Hypertension (2013), 1–6 & 2013 Macmillan Publishers Limited All rights reserved 0950-9240/13 www.nature.com/jhh