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Introduction: Preeclampsia is a serious complication of pregnancy affecting 3-8% of all pregnancies. It increases the morbidity and mortality of both the fetus and the pregnant woman, especially in developing countries. It deleteriously affects several vital organs, including the kidney, heart, liver, brain, and lung. Although, the pathogenesis of preeclampsia has not yet been fully understood, growing evidence suggests that aberrations in the angiogenic factors levels/activity and coagulopathy are responsible for the clinical manifestations of the disease. The common nominator of tissue damage of all these target organs is endothelial injury, which impedes their normal function. At the renal level, glomerular endothelial injury leads to the development of maternal hypertension and proteinuria. Similarly, this disease can cause hepatic and neurologic dysfunction due to vascular damage. The current review summarizes the recent development in the pathogenesis of this disease state with special focus on novel diagnostic biomarkers and their relevance to potential therapeutic options for preeclampsia. Specifically, we will highlight the renal manifestations of the diseases with emphasis on the involvement of angiogenic factors in vascular injury and how restoration of the angiogenic balance affects the renal and cardiovascular outcome of preeclamptic women.

The incidence of both acute and chronic kidney diseases is persistently increasing and is reaching epidemic proportions. Early therapeutic intervention may significantly decrease the morbidity and mortality rates among these patients. However, the lack of early non-invasive biomarkers has hampered our ability to diagnose kidney diseases as early as possible, and subsequently, to initiate timely, effective, and appropriate treatment. Until recently, no biomarker for kidney disease, except for creatinine was available to clinicians in general and nephrologists in particular. Unfortunately, creatinine is an unreliable indicator during acute and chronic changes in kidney function, since serum creatinine concentrations can vary widely with age, gender, muscle mass, muscle metabolism, medications and hydration status. Secondly, serum creatinine concentrations may not change until a significant amount of kidney function (50-60%) has already been lost. In the last few years various specific biomarkers for kidney diseases were discovered and the most reliable representative is neutrophil gelatinase-associated lipocalin (NGAL), which is the focus of this review. Several studies have demonstrated that plasma and urinary NGAL levels increase two hours after the induction of acute kidney injury (AKI) in several clinical situations such as cardiac surgery, radiocontrast nephropathy, kidney transplantation, hemolytic uremic syndrome and critically ill patients in intensive care unit. Serum and urine concentrations of NGAL increase before those of creatinine, making this biomarker a powerful tool for early detection of renal disease, thus hopefully to reduce the high mortality rate among patients with AKI.

Hypertension is the most common risk factor for cardiovascular disease, constituting the most common cause of death in industrialized countries. Therefore, the task of blood pressure reduction has significant importance in reducing vascular damage, myocardial infarctions, kidney damage and incidence of cerebrovascular accidents. The renin-angiotensin-aldosterone system (RAAS) plays a central role in control and function of the cardiovascular and renal systems, and is deeply involved in the pathophysiology of diseases of vasculature, heart, kidneys and others. Therefore, blockade of RAAS by angiotensin converting enzyme (ACE) inhibitors and blockers of angiotensin II type AT1 receptors (ARBs) is widely utilized by clinicians. Indeed, it has long been known that ACE inhibitors and ARBs protect different targets of angiotensin II, due to impedance of the negative effects of the hormone and the inhibition of aldosterone production, which contributes both directly and indirectly to the damages, independent of angiotensin II. Despite this, the morbidity and mortality resulting from the progression of cardiovascular diseases in patients treated with ACE inhibitors or ARBs remain high. As such, over the years, much effort has been dedicated to the development of direct inhibitors of renin. The earliest renin inhibitors, developed 30 years ago were not effective due to their protein nature, which prevents their oral administration and limited their clinical use. In the last decade, several non-protein renin inhibitors which could be given orally were developed, of which Aliskiren is the most well known representative. Due to the fact that neutralization of the RAAS by ACE inhibitors and ARBs has been reviewed at length many times, this review will focus on the renewed subject of renin inhibition. The earliest research, both in humans as well as in animal models, show that Aliskiren has therapeutic potential in treatment of patients with hypertension, cardiovascular disease and renal disease. However, the efficacy of Aliskiren in treating systolic and diastolic hypertension in patients was not better than that obtained using ACE inhibitors or ARBs. Even so, there is no need to lower levels of optimism for potential therapy using direct inhibitors of renin. Current research is still in its early stages and there is a need to remember that it took many years to prove the clinical usefulness of ACE inhibitors, which are now central to treatment of cardiovascular and renal diseases, including hypertension.

Vasopressin, or anti-diuretic hormone, is a peptide hormone that plays an important role in the regulation of extracellular volume and its osmolarity. Increased plasma osmolarity and hypovolemia are the principal physiological stimuli for vasopressin release. The biological effects of vasopressin on its target organs are mediated by two receptors: V1 and V2. V2 is localized to renal tissue and its activation leads to upregulation of aquaporin-2 in the collecting duct allowing the reabsorption of large volumes of water. In contrast, V1 is expressed mainly in blood vessel walls, and its activation results in vascoconstriction. Besides the physiological importance of the vasopressin system, it also plays a crucial role in the pathogenesis of various diseases, including congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone secretion. These clinical syndromes are characterized by enhanced plasma levels of vasopressin, which correlate with the severity of the disease and largely contribute to the development of edema and hyponatremia. Great efforts have been invested in attempting to develop selective and long lasting vasopressin antagonists. However, general medicine and particularly nephrology, suffered from the absence of non-peptide vasopressin blockers that could be taken orally. The last few years have witnessed the development of numerous selective vasopressin antagonists with high bioavailability and long half-lives. Administration of these antagonists to patients with congestive heart failure, cirrhosis, and syndrome of inappropriate antidiuretic hormone secretion substantially enhanced free water excretion and moderately increased serum sodium concentrations. No side effects, except for mild increased thirst sensation, were observed. The present review focuses on the recent developments in vasopressin research, with special emphasize on the development of selective non-peptide antagonists and their clinical use.

The endothelin system plays an important role in the pathophysiology of a variety of cardiovascular diseases including: congestive heart failure, essential and pulmonary hypertension, renal failure, and cerebrovascular disease. The biological effects of endothelin-1 on its target organs are mediated by two receptors: ETA and ETB. It is widely accepted that the vascular, cardiac, and renal adverse effects of ET-1 are mediated by ETA, while activation of ETB receptors leads to beneficial effects such as: attenuating the vascular and cardiac hypertrophic effects of ET-1 as well as the vasodilatory action of this peptide. In the last decade, a whole range of peptide and non-peptide ET-1 antagonists has been developed, some selective to ETA and others nonselective with dual antagonistic activity against both ETA and ETB. Several clinical studies have revealed that ET-1 antagonists are clinically beneficial therapeutic agents for the treatment of several cardiovascular diseases, leading to the approval of bosentan (ETA/ETB antagonist) for the treatment of pulmonary hypertension. The current review will focus on the recent developments in the endothelin field, with special emphasis on the ET-1 antagonist and their clinical use.

Aldosterone, the major mineralocorticoid and most potent sodium retaining hormone in mammals was discovered in 1952 by Simpson and Tait. Since then numerous studies were carried out to explore the mechanisms underlying the biological actions of this steroid hormone, and the physiological effects of aldosterone remained an attractive area of research. The utilization of sophisticated molecular biology techniques led to the identification of genes encoding major components of the aldosterone-regulated sodium reabsorptive pathway, such as mineralocorticoid receptor. 11b-hydroxysteroid dehydrogenase type 2, epithelia Na+ channel, and sgk and Kras genes. It is clear that aberrations in these genes lead to genetic diseases affecting blood pressure and fluid homeostasis. However, in the last decade several clinical and experimental studies have implicated aldosterone in the pathogenesis of cardiovascular dysfunction, especially heart failure. In this context, aldosterone increases the accumulation of collagen in the fibroblast and myocytes of the cardiac tissue leading to fibrosis and cardiac hypertrophy. Blockade of aldosterone receptors by spironolactone substantially reduced the risk of morbidity and death among patients with severe heart failure. The present review summarizes the recent developments in the molecular mechanisms of aldosterone actions and its involvement in the pathogenesis of heart failure.