Inhibition of RAS in diabetic nephropathy

Abstract

Diabetic kidney disease (DKD) is a progressive proteinuric renal disorder in patients with type 1 or type 2 diabetes mellitus. It is a common cause of end-stage kidney disease worldwide, particularly in developed countries. Therapeutic targeting of the renin-angiotensin system (RAS) is the most validated clinical strategy for slowing disease progression. DKD is paradoxically a low systematic renin state with an increased intrarenal RAS activity implicated in its pathogenesis. Angiotensin II (AngII), the main peptide of RAS, is not only a vasoactive peptide but functions as a growth factor, activating interstitial fibroblasts and mesangial and tubular cells, while promoting the synthesis of extracellular matrix proteins. AngII also promotes podocyte injury through increased calcium influx and the generation of reactive oxygen species. Blockade of the RAS using either angiotensin converting enzyme inhibitors, or angiotensin receptor blockers can attenuate progressive glomerulosclerosis in animal models, and slows disease progression in humans with DKD. In this review, we summarize the role of intrarenal RAS activation in the pathogenesis and progression of DKD and the rationale for RAS inhibition in this population.

Keywords: angiotensin II; angiotensin receptor blockers; angiotensin-converting enzyme inhibitors; diabetic kidney disease; renin-angiotensin system.

Figure 1

RAS cascade. Notes: Juxtaglomerular (JG) cells in the kidney activate prorenin and secrete renin into the circulation. Renin hydrolyzes angiotensinogen (AGT) to angiotensin I (AngI) which is subsequently converted by angiotensin converting enzyme (ACE) to angiotensin II (AngII). AngII exerts its action by binding to angiotensin II Types I and II receptors (AT₁R and AT₂R). ACE2 catalyzes the conversion of AngI to angiotensin 1–9 (Ang 1–9) which is subsequently converted to angiotensin 1–7 (Ang 1–7) by ACE. Ang 1–7 also inhibits ACE and opposes AngII signaling. Abbreviation: RAS, renin–angiotensin system.

Figure 2

Hemodynamic changes in diabetic kidney disease (DKD). Notes: Early in the course of diabetes mellitus (DM), there is volume expansion and an increase in sodium (Na) reabsorption from the proximal tubule (PT) mediated by increased insulin production, and the augmented sodium–glucose cotransport leading to increased tubuloglomerular feedback (TGF) mediated afferent arteriolar (AA) dilatation and increased flow rate. This is accompanied by an increased production of local angiotensin II (AngII) augmenting the dilatory effects of TGF on AA. Increased local AngII will cause mesangial cell constriction and efferent arteriolar (EA) vasoconstriction, causing along with the increased flow rate an increased intraglomerular pressure (IGP). This will increase sheer stress and chronically worsens kidney damage.