The Absence of the ACE N-Domain Decreases Renal Inflammation and Facilitates Sodium Excretion during Diabetic Kidney Disease

Abstract

These data indicate that increasing AcSDKP by blocking the ACE N-domain facilitates sodium excretion and ameliorates diabetic kidney disease independent of intrarenal angiotensin II regulation.

Ion channels and transporters in diabetic kidney disease

“…Similarly, analysis of distal tubule transporters revealed increased expression in both total and phosphorylated sodium-chloride cotransporter (NCC), and in subunits of the epithelial Na + channel (ENaC). Diabetic animals exhibited elevations in total αand β-ENaC as well as cleaved forms of αand γ-ENaC (Eriguchi et al, 2018). These data demonstrate that STZ-mediated hypoinsulinemia and hyperglycemia cause upregulation of most major sodium transporters.…”

“…The furosemide-sensitive cotransporter NKCC2 and the thiazide-sensitive cotransporter NCC play important roles in renal salt handling and extracellular volume regulation in the TAL and DCT, respectively. Similar to other sodium transporters, expression of both total and active forms of NKCC2 and NCC is increased under diabetic conditions, which has been reported in several rodent models (Cipriani et al, 2012;Eriguchi et al, 2018;Riazi, Khan, Tiwari, Hu, & Ecelbarger, 2006;Riazi, Maric, & Ecelbarger, 2006). Metformin, an antidiabetic drug that is widely used to treat patients with diabetes mellitus, was shown to increase urinary sodium excretion by reducing phosphorylation of NCC.…”

N‐acetyl‐seryl‐aspartyl‐lysyl‐proline is a valuable endogenous antifibrotic peptide for kidney fibrosis in diabetes: An update and translational aspects

“…In a cross‐over design/double‐blind analysis for a 6‐week study period with a regular or a low‐sodium diet and either lisinopril or lisinopril plus valsartan, sodium restriction was confirmed to increase the plasma level of AcSDKP during either single or dual renin–angiotensin system blockade. Interestingly, a recent report utilizing mice with knockout of the N‐terminal sequence of ACE, which resulted in AcSDKP degradation, found that they showed increased levels of AcSDKP associated with enhanced urine excretion of sodium without alterations in renal angiotensin II levels. The molecular regulation and physiological relevance of the interaction of AcSDKP levels and sodium intake/excretion have not yet been elucidated, and further research is required.…”

N-Acetyl-Seryl-Aspartyl-Lysyl-Proline Mitigates Experimental Colitis Through Inhibition of Intestinal Mucosal Inflammatory Responses via MEK-ERK Signaling

“…Numerous studies have shown that AcSDKP exerts strong protective effects on several diseases involving the brain, heart, liver, and kidney; in part by reducing local inflammatory reactions (Chen et al, 2010;Worou et al, 2015;Zhang et al, 2017;Sharma et al, 2018). Additionally, taking into consideration that AcSDKP is mainly degraded by the Ndomain of angiotensin-converting enzyme (ACE) (Azizi et al, 1996;Eriguchi et al, 2018), several studies reported that the antiinflammatory and anti-fibrotic effects of ACE inhibitors on the heart and kidney, were at least partly mediated by increasing AcSDKP in plasma and tissues (Peng et al, 2007;Chan et al, 2018). Mechanistically, AcSDKP works through modulating multiple aspects of immune responses, including the activation of critical signaling pathways, release of proinflammatory mediators, infiltration of T-cells, and differentiation or migration of macrophages (Sharma et al, 2008;Gonzalez et al, 2014;Zhu et al, 2016;Li et al, 2017).…”