Discovering genetic modifiers of early kidney disease

Kidney disease is a major risk factor for cardiovascular mortality. Multiple genetic and environmental factors provoke susceptibility to kidney disease. We have identified several susceptibility genes using a combination of; high-throughput transcript expression, bioinformatics and renal physiology (1). Historically we found angiotensin converting enzyme (ACE) to be a key modifier of hypertensive renal injury (2). ACE inhibitors have become frontline drugs used everyday in the clinic to tackle hypertension and kidney disease.

Key pathways of macrophage induced kidney damage
Acute antagonism of P2X7 lowers blood pressure (red trace) and improved perfusion of the kidney medula (blue trace)

Research Methods and Objectives

However, the therapeutic need is remains unmet: the prevalence of kidney disease has remained at 8-16% globally. In our recent work we identified multiple adenosine-5’-triphosphate (ATP) activated purine receptors that increase hypertensive renal vascular damage (3). P2X7 is functionally expressed on vascular and inflammatory cell types within the kidney. In addition to this receptor’s role in glomerular inflammation, for example through P2X7 expressing macrophages (Figure 1) we have recently identified its control of blood pressure and kidney blood flow by P2X7 (Figure 2). Our ongoing investigations will determine whether P2X7 antagonists have sufficient efficacy to ameliorate (or even reverse) hypertensive or diabetic kidney disease.

  1. Menzies RI et al. Effect of P2X4 and P2X7 receptor antagonism on the pressure diuresis relationship in rats. Front. Physiol. 2013;4.
  2. Liu X et al. Angiotensin-converting Enzyme Is a Modifier of Hypertensive End Organ Damage. J. Biol. Chem. 284, 15564-15572.
  3. Menzies RI et al. Inhibition of the purinergic P2X7 receptor improves renal perfusion in angiotensin-II-infused rats. Kidney International 88, 1079–1087

Related Researchers

John MullinsRob Menzies, Tim Aitman,  and Matt Bailey


BHF  FS/15/61/31626