Protecting Renal Function in Diabetes

It is therefore “of paramount importance to identify safe, new agents that prevent or delay the initiation and progression of diabetic nephropathy,” they noted.¹

Reviewing the recent research, Lytvyn and colleagues observed that drugs that activate the ACE homologue ACE2, and neprilysin inhibitors, are “promising therapeutic targets to supplement conventional RAAS blockade in diabetic nephropathy.”¹ They also highlighted sodium-glucose cotransporter-2 inhibitors (SGLT2i), renal anti-inflammatory and anti-fibrotic agents and incretin-based drugs as potential kidney-protection therapies.¹

ACE2

Potential new targets for therapy have been identified in the RAAS pathways. In 2000, ACE2 was identified as a homologue of ACE, that is “especially abundant” in the kidneys, where it is believed to moderate oxidative stress and inflammation.¹ ACE2 downregulation is associated with albuminuria and renal tissue damage, and ACE2 “can attenuate the development of DN” in laboratory animal studies, Lytvyn and coauthors reported.¹

“In fact, DN is associated with reduced glomerular and tubular ACE2 expression, and ACE2 activity is associated with glycemic control and glomerular filtration rate in patients with DN,” leading to studies of ACE2 as a promising target for DN prevention and therapy, they noted.¹  “Recombinant ACE2 may provide further synergistic benefits in combination with conventional RAAS inhibition by preventing feedback escape and/or enhancing the generation of Ang 1-7, thereby augmenting vascular protective effects associated with traditional RAAS inhibitors.”

In lab animal studies, the small-molecule ACE2 activators xanthenone and diminazene aceturate increased ACE2 activity and decreased blood pressure, Lytvyn and coauthors reported.¹ But “despite the strong mechanistic rationale for ACE2 renal protection based on animal models, very little is currently known about this emerging class in humans,” they cautioned.¹

SGLT2 inhibition

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) suppress renal hyperfiltration and lower blood sugar concentrations, and may slow the progression of DN.^1,7-10 By helping to reduce glucose reabsorption at the proximal renal tubule, SGLT2i may also attenuate glucose-mediated inflammation and fibrosis.^7,9,10

“Increased filtered glucose load at the proximal tubule during hyperglycemia results in about 36% overexpression of SGLT2 in diabetes,” reported Lytvyn and colleagues.¹ “Consequently, increased reabsorption of sodium at the proximal tubule leads to decreased distal sodium delivery to the macula densa, which is incorrectly sensed as a reduction in effective circulating volume by the juxtaglomerular apparatus leading to down regulation of the tubuloglomerular feedback mechanism,  vasodilation of the afferent renal arterioles, and thus, hyperfiltration characteristic of DN.”

SGLT2 inhibition-mediated increases in sodium transport may also alter the production of adenosine in the kidney, thereby reducing hyperfiltration, at least in laboratory animals.¹