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Summary: Defects in endothelial cells cause deterioration in kidney function and structure. Here, we found that endothelial SIRT3 regulates metabolic reprogramming and fibrogenesis in the kidneys of diabetic mice. By analyzing, gain of function of the SIRT3 gene by overexpression in a fibrotic mouse strain conferred disease resistance against diabetic kidney fibrosis, whereas its loss of function in endothelial cells exacerbated the levels of diabetic kidney fibrosis. Regulation of endothelial cell SIRT3 on fibrogenic processes was due to tight control over the defective central metabolism and linked activation of endothelial-to-mesenchymal transition (EndMT). SIRT3 deficiency in endothelial cells stimulated the TGFβ/Smad3-dependent mesenchymal transformations in renal tubular epithelial cells. These data demonstrate that SIRT3 regulates defective metabolism and EndMT-mediated activation of the fibrogenic pathways in the diabetic kidneys. Together, our findings show that endothelial SIRT3 is a fundamental regulator of defective metabolism regulating health and disease processes in the kidney.

Vascular endothelial growth factor (VEGF) regulates vasculogenesis in physiological and pathological states. We evaluated the role of VEGF single-nucleotide polymorphisms (SNPs) −1154 G/A, −2578 C/A, +936 C/T, and −2549 Ins/Del in chronic allograft nephropathy. Methods: Blood samples were collected before renal transplantation, and DNA was extracted. Genotyping of VEGF SNPs −1154 G/A (rs1570360), −2578 C/A (rs699947), +936 C/T (rs112005313), and −2549 Ins/Del (18bpindel) polymorphisms were carried out. Relative quantification of VEGF-A mRNA expression for 4 VEGF SNPs were quantified by the 2−ΔΔCt algorithm. Kidney allografts were categorized into graft loss (n = 98) and normally functioning (n = 174) groups. Genotype frequencies were calculated using additive, dominant, and recessive models. Hardy−Weinberg Equilibrium was assessed between outcome groups by standard procedure using χ2 analysis. The cumulative allograft survival was estimated by Kaplan−Meier analysis and compared among VEGF genotypes by the log-rank test. Study limitations were the lack of VEGF serum levels, donor-specific antigens, and protocol biopsies. Results: There was an association of AA (hazard ratio = 2.42, P = 0.0001) and CA (hazard ratio = 1.83, P = 0.009) genotypes of −2578 C/A SNP with graft loss. After adjustment for transplant-related covariates, associations of VEGF SNPs −2578 C/A and −2549 Ins/Del with graft failure were found to be significant. There was prolonged graft survival for cases with the CC genotype of VEGF −2578 C/A SNP. The carrier −2578*CC, −1154*GG, and +936*CC genotypes were shown to have a strongly protective association. There was no association with posttransplantation lymphomas. Conclusion: Recipients of kidney allografts possessing low-producing VEGF genotypes are associated with less prolonged graft survival.

Summary: Central nervous system involvement is observed in no more than 10% of patients with systemic tuberculosis. Although CNS tuberculosis is not rare in endemic countries, such as India, intramedullary tuberculosis is not commonly reported. In this study, we report a case of a 40-year-old female who presented with a six-year history of insidious onset, gradually progressive, asymmetric quadriparesis. She was diagnosed with intramedullary tuberculoma at the craniovertebral junction and showed significant clinico-radiological improvement with medical management alone. To the best of our knowledge, this report describes the first case of intramedullary tuberculoma at the craniovertebral junction to be reported. With the increased availability of MRI in developing countries, it is now possible for clinicians to diagnose this condition without performing a biopsy. It is important for the clinicians in developed countries to be highly suspicious of intramedullary tuberculoma, as there has been a resurgence of CNS tuberculosis due to the emergence of the HIV pandemic. Keywords: Intramedullary, Tuberculoma, Craniovertebral junction

Integrin β1 and dipeptidyl peptidase (DPP)-4 play roles in endothelial cell biology. Vascular endothelial growth factor (VEGF)-A inhibits endothelial-to-mesenchymal transition (EndMT) through VEGF-R2, but through VEGF-R1 promotes EndMT by reducing the bioavailability of VEGF-A. Here we tested whether DPP-4-integrin β1 interactions have a role in EndMT in the renal fibrosis of diabetic nephropathy. In streptozotocin-induced fibrotic kidneys in diabetic CD-1 mice, levels of endothelial DPP-4, integrin β1, and phospho-integrin β1 were all higher and associated with plasma cystatin C elevation. The DPP-4 inhibitor linagliptin ameliorated kidney fibrosis, reduced plasma cystatin C levels, and suppressed endothelial levels of DPP-4, integrin β1, and phospho-integrin β1. In cultured endothelial cells, DPP-4 and integrin β1 physically interacted. Suppression of DPP-4 by siRNA was associated with suppression of integrin β1 and vice versa. Knockdown of either integrin β1 or DPP-4 resulted in the silencing of TGF-β2-induced TGF-β receptor heterodimer formation, smad3 phosphorylation, and EndMT. DPP-4 negatively regulated endothelial viability signaling by VEGF-R2 suppression and VEGF-R1 induction in endothelial cells. Thus, DPP-4 and integrin β1 interactions regulate key endothelial cell signal transduction in both physiological and pathological conditions including EndMT. Hence, inhibiting DPP-4 may be a therapeutic target for treating kidney fibrosis in diabetes.