Deacetylation of Septin4 by SIRT2 (Silent Mating Type Information Regulation 2 Homolog-2) Mitigates Damaging of Hypertensive Nephropathy

Abstract

Background: Hypertension can lead to podocyte damage and subsequent apoptosis, eventually resulting in glomerulosclerosis. Although alleviating podocyte apoptosis has clinical significance for the treatment of hypertensive nephropathy, an effective therapeutic target has not yet been identified. The function of septin4, a proapoptotic protein and an important marker of organ damage, is regulated by post-translational modification. However, the exact role of septin4 in regulating podocyte apoptosis and its connection to hypertensive renal damage remains unclear. Methods: We investigated the function and mechanism of septin4 in hypertensive nephropathy to discover a theoretical basis for targeted treatment. Mouse models including Rosa26-Sirt2 (silent mating type information regulation 2 homolog-2)-Flag mice, SIRT2-knockout, and septin4-K174Q mutant mice, combined with proteomic and acetyl proteomics analysis, followed by multiple molecular biological methodologies, were used to demonstrate mechanisms of SIRT2-mediated deacetylation of septin4-K174 in hypertensive nephropathy. Results: Using transgenic septin4-K174Q mutant mice treated with the antioxidant Tempol, we found that hyperacetylation of the K174 site of septin4 exacerbates Ang II (angiotensin II)– induced hypertensive renal injury resulting from oxidative stress. Proteomics and Western blotting assays indicated that septin4-K174Q activates the cleaved-PARP1 (poly [ADP-ribose] polymerase family, member 1)-cleaved-caspase3 pathway. In septin4-knockdown human renal podocytes, septin4-K174R, which mimics deacetylation at K174, rescues podocyte apoptosis induced by Ang II. Immunoprecipitation and mass spectrometry analyses identified SIRT2 as a deacetylase that interacts with the septin4 GTPase domain and deacetylates septin4-K174. In Sirt2-deficient mice and SIRT2-knockdown renal podocytes, septin4-K174 remains hyperacetylated and exacerbates hypertensive renal injury. By contrast, in Rosa26-Sirt2-Flag (SIRT2-TG) mice and SIRT2-knockdown renal podocytes reexpressing wild-type SIRT2, septin4-K174 is hypoacetylated and mitigates hypertensive renal injury. Conclusions: Septin4, when activated through acetylation of K174 (K174Q), promotes hypertensive renal injury. Septin4-K174R, which mimics deacetylation by SIRT2, inhibits the cleaved-PARP1-cleaved-caspase3 pathway. Septin4-K174R acts as a renal protective factor, mitigating Ang II–induced hypertensive renal injury. These findings indicate that septin4-K174 is a potential therapeutic target for the treatment of hypertensive renal injury.

Mechanisms of inflammation modulation by different immune cells in hypertensive nephropathy

“…Recent studies have shown that septin4 promotes hypertensive kidney injury by activating the acetylation of K174 (K174Q). Septin4–K174R is one of the renoprotective factors that ameliorates Ang II-induced hypertensive kidney injury ( 47 ). In addition, an increase in blood pressure leads to arterial stiffness, which eventually affects the arteries and causes glomerular lesions ( 48 ).…”

Meet the Novel Players in Hypertensive Kidney Disease: Septin4 and SIRT2

“…8 Meanwhile, the specific role of SIRT2 in kidney disease remains unclear. In the article by Zhang et al, 4 authors proposed that SIRT2-mediated deacetylation of Septin4-K174 attenuates hypertensive renal injury. Indeed, they showed that Sirt2 depletion in mice and SIRT2-knockdown in renal podocytes, Septin4-K174 remains hyperacetylated, and this exacerbates hypertensive renal injury.…”

“…7 Septin4 expression is regulated by the Notch pathway and ubiquitination at K174 promote degradation of Septin4 through the ubiquitin-proteasome system. 6 In this article, 4 authors proposed that posttranslational modification of Septin4 by acetylation at K174 promotes hypertensive renal injury. Indeed, they found that Septin4-K174Q acetylation mimetic mutation in mice exacerbates angiotensin II-induced hypertensive renal injury and superoxide scavenger TEMPOL (4-Hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl) protects from oxidative stress and significantly reduces the damaging effects in Septin4-K174Q mice.…”

“…PubMed database shows 85 491 publication on this subject; nevertheless, major aspects of clinical hypertensive renal disease remain poorly understood, 3 and any new ideas are very important to consider. In the article by Zhang et al, 4 authors proposed a novel role of Septin4 acetylation promotes kidney disease, and deacetylation of Septin4 by nicotinamide adenine dinucleotide (NAD)-dependent deacetylase SIRT2 (sirtuin 2) mitigates damaging effects of hypertensive nephropathy (Figure). What are the Septin4 and SIRT2?…”

“…In summary, Zhang et al 4 need to be commended for providing a first hint regarding the potential therapeutic effects for targeting SIRT2-Septin4 axes. This, however, may be just a tip of the iceberg, and we should be carefully investigating what is beneath the water.…”