Homoarginine ameliorates diabetic nephropathy independent of nitric oxide synthase-3

AUTHORS

Michael D. Wetzel, Kristen Stanley, Soumya Maity, Muniswamy Madesh, Jean C. Bopassa, Alaa S. Awad

ABSTRACT

Recently we showed that homoarginine supplementation confers kidney protection in diabetic mouse models. In this study we tested whether the protective effect of homoarginine is nitric oxide synthase-3 (NOS3)-independent in diabetic nephropathy (DN). Experiments were conducted in NOS3 deficient (NOS3−/−) mice and their wild type littermate using multiple low doses of vehicle or streptozotocin and treated with homoarginine via drinking water for 24 weeks. Homoarginine supplementation for 24 weeks in diabetic NOS3−/− mice significantly attenuated albuminuria, increased blood urea nitrogen, histopathological changes and kidney fibrosis, kidney fibrotic markers, and kidney macrophage recruitment compared with vehicle-treated diabetic NOS3−/− mice. Furthermore, homoarginine supplementation restored kidney mitochondrial function following diabetes. Importantly, there were no significant changes in kidney NOS1 or NOS2 mRNA expression between all groups. In addition, homoarginine supplementation improved cardiac function and reduced cardiac fibrosis following diabetes. These data demonstrate that the protective effect of homoarginine is independent of NOS3, which will ultimately change our understanding of the mechanism(s) by which homoarginine induce renal and cardiac protection in DN. Homoarginine protective effect in DN could be mediated via improving mitochondrial function.

Incorporation of nanosized calcium silicate improved osteointegration of polyetheretherketone under diabetic conditions

AUTHORS

Rui Ma, Yongwei Li, Jialin Wang, Pei Yang, Kunzheng Wang & Wei Wang

ABSTRACT

Diabetes can impair osteoblastic functions and negatively interfere with osteointegration at the bone/implant interface. Previously, we prepared a nanosized calcium silicate (CS) incorporated-polyetheretherketone (PK) biocomposite (CS/PK) and found that the CS/PK composite exhibited enhanced osteoblast functions in vitro and osteointegration in vivo, but its bioperformance under diabetic conditions remained elusive. In this study, MC3T3-E1 cells incubated on CS/PK and PK samples were subjected to diabetic serum (DS) and normal serum (NS); cell attachment, morphology, spreading, proliferation, and osteogenic differentiation were compared to assess in vitro osteoblastic functions on the surfaces of different materials. An in vivo test was performed on diabetic rabbits implanted with CS/PK or PK implants into the cranial bone defect to assess the osteointegration ability of the implants. In vitro results showed that diabetes inhibited osteoblastic functions evidenced by impaired morphology and spreading, and decreased attachment, proliferation, and osteogenic differentiation compared with the findings under normal conditions. Notably, CS/PK ameliorated osteoblastic disfunction under diabetic conditions in vitro. In vivo results from micro-CT and histologic examinations revealed that rabbits with CS/PK implants exhibited improved osteointegration at the bone/implant interface under diabetic conditions compared with PK. Therefore, the CS/PK composite improved the impaired osteointegration induced by diabetes and is a promising orthopedic or craniofacial implant material that may obtain good clinical performance in diabetic patients.

Peri-implant defect regeneration in the diabetic pig: a preclinical study

Authors

Cornelius von Wilmowsky, Karl Andreas Schlegel, Christoph Baran, Emeka Nkenke, Friedrich Wilhelm Neukam, Tobias Moest

Abstract

Objectives
The study aims to establish a peri-implant dehiscence-type bone defect in a diabetic animal model of human bone repair and to quantify the influence of diabetes on peri-implant bone regeneration.

Material and methods
Experimental diabetes was induced in three domestic pigs by streptozotocin. Three animals served as healthy controls. After 12 months four standardized peri-implant dehiscence bone defects were surgically created in the ramus mandibulae. The animals were sacrificed after 90 days. Samples were histologically analyzed to quantify new bone height (NBH), bone-to-implant-contact (BIC), area of newly formed bone (NFB), bone-density (BD), and bone mineralization (BM) in the prepared defect (- D) and in a local control region (-L).

Results
After 90 days, diabetic animals revealed a significantly lower BIC (p=0.037) and BD (p=0.041) in the defect area (-D). NBH and BM-D differences within the groups were not significant (p>0.05). Significant more NFB was measured in the healthy control group (p=0.046). In the region of local bone BIC-L was significant less in the diabetic group (p=0.028). In the local control region BD-L and BM-L was lower in the diabetic group compared to the healthy control animals (p>0.05).

Conclusion
Histological evidence indicates impaired peri-implant defect regeneration in a diabetic animal model.

Link to Article

http://dx.doi.org/10.1016/j.jcms.2016.04.002

Hypohalous Acids Contribute to Renal Extracellular Matrix Damage in Experimental Diabetes

Authors

Kyle L. Brown, Carl Darris, Kristie Lindsey Rose, Otto A. Sanchez, Hartman Madu, Josh Avance, Nickolas Brooks, Ming-Zhi Zhang, Agnes Fogo, Raymond Harris, Billy G. Hudson and Paul Voziyan

Abstract

In diabetes, toxic oxidative pathways are triggered by persistent hyperglycemia and contribute to diabetic complications. A major proposed pathogenic mechanism is accumulation of protein modifications called advanced glycation end products (AGEs). However, other non-enzymatic post-translational modifications may also contribute to pathogenic protein damage in diabetes. We demonstrate that hypohalous acid-derived modifications of renal tissues and extracellular matrix (ECM) proteins are significantly elevated in experimental diabetic nephropathy. Moreover, diabetic renal ECM shows diminished binding of α1β1 integrin consistent with modification of collagen IV by hypochlorous (HOCl) and hypobromous (HOBr) acids. NC1 hexamers, key connection modules of collagen IV networks, are modified via oxidation and chlorination of tryptophan and bromination of tyrosine residues. Chlorotryptophan, a relatively minor modification, has not been previously found in proteins. In the NC1 hexamers isolated from diabetic kidneys, levels of HOCl-derived oxidized and chlorinated tryptophan residues W28 and W192 are significantly elevated compared to non-diabetic controls. Molecular dynamics simulations predicted more relaxed NC1 hexamer tertiary structure and diminished assembly competence in diabetes; this was confirmed using limited proteolysis and denaturation/refolding. Our results suggest that hypohalous acid-derived modifications of renal ECM and specifically collagen IV networks contribute to functional protein damage in diabetes.

Link To Article

http://dx.doi.org/10.2337/db14-1001

An insulin-sensitizing thiazolidinedione, which minimally activates PPARγ, does not cause bone loss

Authors

Tomohiro Fukunaga, Wei Zou, Nidhi Rohatgi, Jerry R. Colca and Steven L. Teitelbaum

Abstract

Rosiglitazone is an insulin-sensitizing thiazolidinedione (TZD) which activates the transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ). While rosiglitazone effectively treats type II diabetes mellitus (T2DM), it carries substantial complications including increased fracture risk. This predisposition to fracture is consistent with the fact that PPARγ preferentially promotes formation of adipocytes at the cost of osteoblasts. Rosiglitazone-activated PPARγ, however, also stimulates osteoclast formation. A new TZD analog with low affinity for binding and activation of PPARγ but whose insulin-sensitizing properties mirror those of rosiglitazone, has been recently developed. Because of its therapeutic implications, we investigated the effects of this new TZD analog (MSDC-0602) on skeletal homeostasis, in vitro and in vivo. Confirming it activates the nuclear receptor in osteoclasts, rosiglitazone enhances expression of the PPARγ target gene, CD36. MSDC-0602, in contrast, minimally activates PPARγ and does not alter CD36 expression in the bone resorptive cells. Consistent with this finding, rosiglitazone increases RANKL-induced osteoclast differentiation and number whereas MSDC-0602 fails to do. To determine if this new TZD analog is bone sparing, in vivo, we fed adult male C57BL/6 mice MSDC-0602 or rosiglitazone. 6-months of a rosiglitazone diet results in a 35% decrease in bone mass with increased number of osteoclasts whereas that of MSDC-0602 fed mice is indistinguishable from control. Thus PPARγ-sparing eliminates the skeletal side effects of TZDs while maintaining their insulin-sensitizing properties.

Link To Article

http://dx.doi.org/10.1002/jbmr.2364