TGF-β signaling plays an important role in the pathogenesis and progression of chronic kidney disease (CKD). Smad3, a transcription factor, is a critical fibrogenic mediator of TGF-β. Sirt1 is a NAD(+) -dependent deacetylase that has been reported to modify a number of transcription factors to exert certain beneficial health effects. This study examined the effect of Sirt1 on Smad3 and its role in CKD. Resveratrol attenuated the expression of extracelluar matrix proteins in both the remnant kidney of 5/6th nephrectomized rats and cultured mesangial cells (MMCs) exposed to TGF-β1. The effect of resveratrol was substantially attenuated in cultured MMCs for which Sirt1 had been knocked down by an shRNA lentivirus. Overexpression of Sirt1 attenuated TGF-β1-induced extracelluar matrix expression in cultured cells. Co-immunoprecipitation studies suggested that Sirt1 could bind with Smad3. Resveratrol treatment enhanced this binding and reduced acetylation levels of Smad3. Resveratrol inhibited the transcription activity of Smad3. Knockdown of Sirt1 increased acetylated Smad3 and substantially enhanced the transcriptional activity following TGF-β1. Finally, Sirt1 deficiency aggravated renal function damage and markedly enhanced fibrosis in the remnant kidney of 5/6 nephrectomized mice. Taken together, these results identify Sirt1 as an important protective factor for renal fibrosis in a CKD rodent model, and the protective function of Sirt1 is attributable to its action on TGF-β/Smad3 signaling. Therefore, we suggest that Sirt1 may be a potential therapeutic target for the treatment of CKD.

The rapid growth of an aging population creates challenges regarding age-related diseases, including AKI, for which both the prevalence and death rate increase with age. The molecular mechanism by which the aged kidney becomes more susceptible to acute injury has not been completely elucidated. In this study, we found that, compared with the kidneys of 3-month-old mice, the kidneys of 20-month-old mice expressed reduced levels of the renal protective molecule sirtuin 1 (SIRT1) and its cofactor NAD Supplementation with nicotinamide mononucleotide (NMN), an NAD precursor, restored renal SIRT1 activity and NAD content in 20-month-old mice and further increased both in 3-month-old mice. Moreover, supplementation with NMN significantly protected mice in both age groups from cisplatin-induced AKI. SIRT1 deficiency blunted the protective effect of NMN, and microarray data revealed that c-Jun N-terminal kinase (JNK) signaling activation associated with renal injury in SIRT1 heterozygotes. , SIRT1 attenuated the stress response by modulating the JNK signaling pathway, probably the deacetylation of a JNK phosphatase, DUSP16. Taken together, our findings reveal SIRT1 as a crucial mediator in the renal aging process. Furthermore, manipulation of SIRT1 activity by NMN seems to be a potential pharmaceutical intervention for AKI that could contribute to the precise treatment of aged patients with AKI.

Objective: This study examined the expression of renal phospholipase A₂ receptor (PLA₂R) in idiopathic and secondary membranous nephropathy (MN). Methods: Patients with biopsy-proven MN and non-MN were enrolled. Renal PLA₂R was examined using an anti-PLA₂R antibody (anti-PLA₂R-Ab), and circulating PLA₂R-Ab was detected by indirect immunofluorescence. Results: Renal PLA₂R was detected along the capillary loop in 84% patients with idiopathic MN but not in those with any other primary glomerulonephritis. Only 1 of 38 patients with class V lupus nephritis showed renal PLA₂R positive. In hepatitis B virus-associated MN (HBV-MN), 64% showed renal PLA₂R positive, and PLA₂R overlapped with HBsAg along the capillary loop. In addition, renal PLA₂R positivity was closely associated with serum PLA₂R-Ab. Renal PLA₂R positive was present in all the patients with serum PLA₂R-Ab positive and in 53% of patients with serum PLA₂R-Ab negative. However, in patients with renal PLA₂R negative, serum PLA₂R-Ab was all negative. Conclusion: Renal biopsy PLA₂R positivity was common in idiopathic MN and HBV-MN but rare in lupus-associated MN, and it was closely associated with serum PLA₂R-Ab production. Further studies examining the association between PLA₂R and HBV-MN may shed light on the mechanism of idiopathic MN or HBV-MN.