Hypertension is a direct consequence of obesity and one whose prevalence is increasing rapidly with the growing obesity epidemic. Hypertension also contributes significantly to morbidity and mortality in today?s society while increasing healthcare expenditures. However, our knowledge of the pathophysiologic changes in obesity which promote hypertension remains incomplete. Better understanding these processes is crucial to devising new treatment strategies. Obesity related hypertension is in large part due to increased sodium retention which in turn occurs through changes in expression and activity of sodium channels in the nephron. ENaC is one such important channel in the distal convoluted tubules and collecting ducts. While several mediators such as increased angiotensin II (Ang II), mineralocorticoid activity, and inflammatory cytokines have been implicated in increasing ENaC activity in the setting of obesity, we believe that additional factors may be involved. The (pro)renin receptor (PRR) is a protein expressed in multiple kidney structures including the distal nephron and whose expression is increased by inflammation. Although initially proposed as a component of the renin- agniotensin-aldosterone system (RAAS) that increases activity of renin and prorenin, PRR is now known to have RAAS independent intracellular signaling properties. This includes activation of the PI3K/Akt/mTOR pathway. Recent work by our laboratory and others have demonstrated an Ang II independent ability of PRR to upregulate the ?-ENaC subunit under normal and low salt conditions. What is not known, however, is whether this relationship plays a significant role in obesity related hypertension. The central hypothesis of this project is therefore that, in obesity, increased renal PRR upregulates ?- ENaC expression and activity, leading to sodium retention and promoting hypertension.
Two specific aims are proposed.
Aim 1 will test whether PRR induces hypertension through ?-ENaC during obesity using an inducible nephron specific PRR knockout mouse.
Aim 2 will test in mouse inner medullary collecting duct cells whether inflammatory cytokines that are present in obesity increase PRR expression, leading to increased ENaC activity via the PI3K/Akt/mTOR/serum and glucocorticoid-inducible kinase isoform 1 (SGK-1) signaling pathway. The knowledge gained from the proposed studies could potentially help develop exciting new therapeutic strategies for prevention and treatment of obesity induced hypertension.
Obesity related hypertension is an increasingly prevalent issue facing our society today and one which is associated with numerous adverse health outcomes. This project will demonstrate the role of the (pro)renin receptor (PRR) in altering kidney function to produce obesity related hypertension. Outcomes from this research will reveal new approaches for developing therapies to prevent and treat obesity induced hypertension.
| Quadri, Syed S; Culver, Silas; Siragy, Helmy M (2018) Prorenin receptor mediates inflammation in renal ischemia. Clin Exp Pharmacol Physiol 45:133-139 |
