Hypertension is one of the prominent chronic diseases in the world. One third adult population of the world suffers from hypertension. According to a report from global burden of disease (GBD), hypertension is the number one global risk factor for morbidity and mortality, pushing behind alcohol consumption, smoking and malnutrition. Hypertension leads to various reno-cardiovascular diseases such as stoke, congestive heart failure as well as progression of chronic renal disease such as End Stage Renal Disease (ESRD). Chronic kidney disease (CKD) and ESRD associated with hypertension is increasing worldwide and it has been found that number of patients suffering from ESRD has increased by 18% between 2000 and 2007.
Podocytes are highly differentiated visceral epithelial cells located in glomerulus of kidney and are vital components of glomerular filtration. It comprises of cell body and octopus like foot processes which surround the glomerular capillaries. Foot processes interlink with each other to form a meshwork of proteins called slit diagram. Podocytes are covered with thick negatively charged glycocalyx layer which help to maintain individual physical structure due to electrostatic repulsive force. Podocytes form glomerular filtration barrier (GFB) along with glomerular basement membrane (GBM) and fenestrated endothelium monolayers. GFB acts as size and charge selective sieve which allows passage of electrolytes, cationic molecules and small solutes but restrict the leakage of anionic molecules and macromolecules such as albumin.
Due to alteration, damage or loss of podocyte, the integrity of GFB becomes fragile which results leakage of macromolecules, such as protein out of glomerulus and into urine. This phenomenon is called proteinuria or albuminuria.
The sympathetic nervous system (SNS) has a significant contribution in the maintenance of blood pressure and sympathetic overactivity has been considered as a predecessor of hypertension and a major contributor of renal disease like CKD. Sympathetic hyperactivity causes elevated arterial blood pressure and prompt damage of the arteries which subsequently lead to various cardiovascular complications such as chronic congestive heart failure, asymptomatic left ventricular dysfunction (ALVD) and end stage renal disease. Many clinical studies suggested that hypertension is a major risk factor for the progression of ESRD. It has been observed that patient with ESRD have elevated plasma norepinephrine level along with intense activity of sympathetic nervous system. So one can easily interpret that increased sympathetic nervous activity accompanied with hypertension might have a significant influence on the initiation and progression of renal injury. Masuo et al. showed that future renal dysfunction of a healthy normotensive person can be anticipated from sympathetic overactivity or increased plasma norepinephrine level.
Sympathetic neurons are part of adrenergic system which innervates many organs and tissues and release neurotransmitters which directly interact with adrenoceptors. Adrenoceptors are G protein couple receptors, act as an intermediary between endogenous catecholamines such as norepinephrine, epinephrine and a broad range of effector cells which are responsible for initiation and maintenance of various biological and pharmacological effects of sympathetic nervous system. There are two major types of adrenoceptors, alpha (α) adrenoceptor and beta (β) adrenoceptor. Each of these adrenoceptors is further divided into various subtypes. Up to date, nine subtypes of adrenoceptors have been identified but so far only four of them (alpha1, alpha2, beta1, beta2) have medical significance.
Beta1 adrenoceptors are predominantly located on heart and cerebral cortex and are responsible for stimulatory effects. They have similar affinity for both epinephrine and norepinephrine. On the other hand, Beta2 adrenoceptors are primarily present in lungs, cerebellum and certain region of kidney. These receptors are responsible for inhibitory effect and cause dilation of the vessels and bronchia. Beta2 adrenoceptors have higher affinity towards norepinephrine compare to epinephrine. Activation of beta receptor by endogenous or exogenous agonist leads to increase in intracellular cAMP which can exert excitatory or inhibitory action, depending on the specification of cell type.
Alpha1 adrenoceptors are G protein couple receptors coupled with Gq protein. Interaction of alpha1 adrenoceptor with endogenous agonist such as norepinephrine activates phospholipase C enzyme which subsequently responsible for the increased production of inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 stimulates calcium release from endoplasmic reticulum via interaction with IP3 receptor whereas DAG activates protein kinase C. High calcium concentration and activated protein kinase ultimately lead to vascular smooth muscle constriction.
