Frank Brosius

Interests

Research

• identification of effective treatments and biomarkers for diabetic complications using systems biology and translational approaches• how glucose uptake promotes specific cellular signaling responses that lead to disease responses in diabetic kidney disease and other diabetic complications• testing new concepts of human diabetic kidney disease and its treatment in robust mouse models that his laboratory has generated and validated• testing small molecules for treatment of diabetic kidney disease in randomized controlled trials

Teaching

Renal physiologyClinical Nephrology

Courses

No activities entered.

Scholarly Contributions

Journals/Publications

• Brosius, F. C., & Vandvik, P. O. (2021). Cardioprotection with Yet Another SGLT2 Inhibitor - An Embarrassment of Riches. The New England journal of medicine, 384(2), 179-181.
• Brosius, F. C., Cherney, D., Gee, P. O., Harris, R. C., Kliger, A. S., Tuttle, K. R., Quaggin, S. E., & , D. A. (2021). Transforming the Care of Patients with Diabetic Kidney Disease. Clinical journal of the American Society of Nephrology : CJASN, 16(10), 1590-1600.
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  Diabetes and its associated complications pose an immediate threat to humankind. Diabetic kidney disease is one of the most devastating complications, increasing the risk of death more than ten-fold over the general population. Until very recently, the only drugs proven and recommended to slow the progression of diabetic kidney disease were angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers, which act by inhibiting the renin-angiotensin system. Despite their efficacy as kidney and cardiovascular protective therapies and as antihypertensive agents, renin-angiotensin system inhibitors have been grossly underutilized. Moreover, even when renin-angiotensin system inhibitors are used, patients still have a high residual risk of diabetic kidney disease progression. Finally, the kidney-protective effect of renin-angiotensin system inhibitors has been categorically demonstrated only in patients with macroalbuminuria included in the Irbesartan Diabetic Nephropathy Trial (IDNT) and Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trials, not in other individuals. The lack of new therapies to treat diabetic kidney disease over the past 2 decades has therefore represented a tremendous challenge for patients and health care providers alike. In recent years, a number of powerful new therapies have emerged that promise to transform care of patients with diabetes and kidney disease. The challenge to the community is to ensure rapid implementation of these treatments. This white paper highlights advances in treatment, opportunities for patients, challenges, and possible solutions to advance kidney health, and introduces the launch of the Diabetic Kidney Disease Collaborative at the American Society of Nephrology, to aid in accomplishing these goals.
• Eid, S. A., Hinder, L. M., Zhang, H., Eksi, R., Nair, V., Eddy, S., Eichinger, F., Park, M., Saha, J., Berthier, C. C., Jagadish, H. V., Guan, Y., Pennathur, S., Hur, J., Kretzler, M., Feldman, E. L., & Brosius, F. C. (2021). Gene expression profiles of diabetic kidney disease and neuropathy in eNOS knockout mice: Predictors of pathology and RAS blockade effects. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 35(5), e21467.
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  Diabetic kidney disease (DKD) and diabetic peripheral neuropathy (DPN) are two common diabetic complications. However, their pathogenesis remains elusive and current therapies are only modestly effective. We evaluated genome-wide expression to identify pathways involved in DKD and DPN progression in db/db eNOS-/- mice receiving renin-angiotensin-aldosterone system (RAS)-blocking drugs to mimic the current standard of care for DKD patients. Diabetes and eNOS deletion worsened DKD, which improved with RAS treatment. Diabetes also induced DPN, which was not affected by eNOS deletion or RAS blockade. Given the multiple factors affecting DKD and the graded differences in disease severity across mouse groups, an automatic data analysis method, SOM, or self-organizing map was used to elucidate glomerular transcriptional changes associated with DKD, whereas pairwise bioinformatic analysis was used for DPN. These analyses revealed that enhanced gene expression in several pro-inflammatory networks and reduced expression of development genes correlated with worsening DKD. Although RAS treatment ameliorated the nephropathy phenotype, it did not alter the more abnormal gene expression changes in kidney. Moreover, RAS exacerbated expression of genes related to inflammation and oxidant generation in peripheral nerves. The graded increase in inflammatory gene expression and decrease in development gene expression with DKD progression underline the potentially important role of these pathways in DKD pathogenesis. Since RAS blockers worsened this gene expression pattern in both DKD and DPN, it may partly explain the inadequate therapeutic efficacy of such blockers.
• Eid, S. A., O'Brien, P. D., Hinder, L. M., Hayes, J. M., Mendelson, F. E., Zhang, H., Narayanan, S., Abcouwer, S. F., Brosius, F. C., Pennathur, S., Savelieff, M. G., & Feldman, E. L. (2021). Differential effects of minocycline on microvascular complications in murine models of type 1 and type 2 diabetes. Journal of translational science, 7(1).
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  Diabetes is a global healthcare problem associated with enormous healthcare and personal costs. Despite glucose lowering agents that control glycaemia, both type 1 (T1D) and type (T2D) diabetes patients often develop microvascular complications that increase morbidity and mortality. Current interventions rely on careful glycemic control and healthy lifestyle choices, but these are ineffective at reversing or completely preventing the major microvascular complications, diabetic peripheral neuropathy (DPN), diabetic retinopathy (DR), and diabetic kidney disease (DKD). Minocycline, a tetracycline antibiotic with anti-inflammatory and anti-apoptotic properties, has been proposed as a protective agent in diabetes. However, there are no reported studies evaluating the therapeutic efficacy of minocycline in T1D and T2D models for all microvascular complications (DPN, DR, and DKD). Therefore, we performed metabolic profiling in streptozotocin-induced T1D and db/db T2D models and compared the efficacy of minocycline in preventing complications to that of insulin and pioglitazone in both models. Minocycline partially ameliorated DR and DKD in T1D and T2D animals, but was less effective than insulin or pioglitazone, and failed to improve DPN in either model. These results suggest that minocycline is unlikely to improve outcomes beyond that achieved with current available therapies in patients with T1D or T2D associated microvascular complications.
• Marx, N., Ryden, L., Brosius, F., Ceriello, A., Cheung, M., Cosentino, F., Green, J., Kellerer, M., Koob, S., Kosiborod, M., Prashant Nedungadi, T., Rodbard, H. W., Vandvik, P. O., Ji, L., Sheu, W. H., Standl, E., & Schnell, O. (2021). Towards living guidelines on cardiorenal outcomes in diabetes: A pilot project of the Taskforce of the Guideline Workshop 2020. Diabetes research and clinical practice, 177, 108870.
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  In June 2020, the Taskforce of the Guideline Workshop 2019 convened via teleconferencing to initiate a pilot project that demonstrates the various processes and considerations involved in developing high-quality, evidence-based clinical practice guidelines for the medical management of individuals with type 2 diabetes (T2D) and its associated comorbidities, including cardiovascular disease (CVD) and chronic kidney disease (CKD). The goal of the pilot project was to create evidence-based guidelines for use of sodium-glucose transport protein 2 inhibitors (SGLT2-I) when managing very high risk T2D patients, evidenced by the presence of both CVD and CKD. For this purpose the Taskforce represented a guideline panel and made use of synthesized evidence from an ongoing BMJ Rapid Recommendations project on SGLT2-I and GLP-1 receptor agonists. Results from the Taskforce pilot project demonstrated the value, feasibility and utility of using a step-wise approach to identifying and grading evidence and then developing actionable recommendations for utilizing SGLT2-I in this at-risk T2D population. This report describes the various steps involved in the process and explains how it can be utilized to rapidly develop recommendations in a format that is easy to use and can be quickly updated as new evidence becomes available, also within the emerging concept of living guidelines.
• Sas, K. M., Lin, J., Wang, C. H., Zhang, H., Saha, J., Rajendiran, T. M., Soni, T., Nair, V., Eichinger, F., Kretzler, M., Brosius, F. C., Michailidis, G., & Pennathur, S. (2021). Renin-angiotensin system inhibition reverses the altered triacylglycerol metabolic network in diabetic kidney disease. Metabolomics : Official journal of the Metabolomic Society, 17(7), 65.
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  Dyslipidemia is a significant risk factor for progression of diabetic kidney disease (DKD). Determining the changes in individual lipids and lipid networks across a spectrum of DKD severity may identify lipids that are pathogenic to DKD progression.
• Tuttle, K. R., Brosius, F. C., Cavender, M. A., Fioretto, P., Fowler, K. J., Heerspink, H. J., Manley, T., McGuire, D. K., Molitch, M. E., Mottl, A. K., Perreault, L., Rosas, S. E., Rossing, P., Sola, L., Vallon, V., Wanner, C., & Perkovic, V. (2021). SGLT2 Inhibition for CKD and Cardiovascular Disease in Type 2 Diabetes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation. American journal of kidney diseases : the official journal of the National Kidney Foundation, 77(1), 94-109.
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  Diabetes is the most frequent cause of chronic kidney disease (CKD), leading to nearly half of all cases of kidney failure requiring replacement therapy. The principal cause of death among patients with diabetes and CKD is cardiovascular disease (CVD). Sodium/glucose cotransporter 2 (SGLT2) inhibitors were developed to lower blood glucose levels by inhibiting glucose reabsorption in the proximal tubule. In clinical trials designed to demonstrate the CVD safety of SGLT2 inhibitors in type 2 diabetes mellitus (T2DM), consistent reductions in risks for secondary kidney disease end points (albuminuria and a composite of serum creatinine doubling or 40% estimated glomerular filtration rate decline, kidney failure, or death), along with reductions in CVD events, were observed. In patients with CKD, the kidney and CVD benefits of canagliflozin were established by the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial in patients with T2DM, urinary albumin-creatinine ratio>300mg/g, and estimated glomerular filtration rate of 30 to
• Tuttle, K. R., Brosius, F. C., Cavender, M. A., Fioretto, P., Fowler, K. J., Heerspink, H. J., Manley, T., McGuire, D. K., Molitch, M. E., Mottl, A. K., Perreault, L., Rosas, S. E., Rossing, P., Sola, L., Vallon, V., Wanner, C., & Perkovic, V. (2021). SGLT2 Inhibition for CKD and Cardiovascular Disease in Type 2 Diabetes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation. Diabetes, 70(1), 1-16.
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  Diabetes is the most frequent cause of chronic kidney disease (CKD), leading to nearly half of all cases of kidney failure requiring replacement therapy. The principal cause of death among patients with diabetes and CKD is cardiovascular disease (CVD). Sodium/glucose cotransporter 2 (SGLT2) inhibitors were developed to lower blood glucose levels by inhibiting glucose reabsorption in the proximal tubule. In clinical trials designed to demonstrate the CVD safety of SGLT2 inhibitors in type 2 diabetes mellitus (T2DM), consistent reductions in risks for secondary kidney disease end points (albuminuria and a composite of serum creatinine doubling or 40% estimated glomerular filtration rate decline, kidney failure, or death), along with reductions in CVD events, were observed. In patients with CKD, the kidney and CVD benefits of canagliflozin were established by the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial in patients with T2DM, urinary albumin-creatinine ratio >300 mg/g, and estimated glomerular filtration rate of 30 to
• Wu, L., Liu, C., Chang, D. Y., Zhan, R., Sun, J., Cui, S. H., Eddy, S., Nair, V., Tanner, E., Brosius, F. C., Looker, H. C., Nelson, R. G., Kretzler, M., Wang, J. C., Xu, M., Ju, W., Zhao, M. H., Chen, M., & Zheng, L. (2021). Annexin A1 alleviates kidney injury by promoting the resolution of inflammation in diabetic nephropathy. Kidney international, 100(1), 107-121.
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  Since failed resolution of inflammation is a major contributor to the progression of diabetic nephropathy, identifying endogenously generated molecules that promote the physiological resolution of inflammation may be a promising therapeutic approach for this disease. Annexin A1 (ANXA1), as an endogenous mediator, plays an important role in resolving inflammation. Whether ANXA1 could affect established diabetic nephropathy through modulating inflammatory states remains largely unknown. In the current study, we found that in patients with diabetic nephropathy, the levels of ANXA1 were upregulated in kidneys, and correlated with kidney function as well as kidney outcomes. Therefore, the role of endogenous ANXA1 in mouse models of diabetic nephropathy was further evaluated. ANXA1 deficiency exacerbated kidney injuries, exhibiting more severe albuminuria, mesangial matrix expansion, tubulointerstitial lesions, kidney inflammation and fibrosis in high fat diet/streptozotocin-induced-diabetic mice. Consistently, ANXA1 overexpression ameliorated kidney injuries in mice with diabetic nephropathy. Additionally, we found Ac2-26 (an ANXA1 mimetic peptide) had therapeutic potential for alleviating kidney injuries in db/db mice and diabetic Anxa1 knockout mice. Mechanistic studies demonstrated that intracellular ANXA1 bound to the transcription factor NF-κB p65 subunit, inhibiting its activation thereby modulating the inflammatory state. Thus, our data indicate that ANXA1 may be a promising therapeutic approach to treating and reversing diabetic nephropathy.
• Cleveland, K. H., Brosius III, F., & Schnellmann, R. G. (2020). Regulation of mitochondrial dynamics and energetics in the diabetic renal proximal tubule by the β2-adrenergic receptor agonist formoterol, Am J Physiol Renal Physiol. 2020 Nov 1;319(5):F773-F779. Am J Physiol, 319, F773-F779.
• Cleveland, K. H., Brosius, F. C., & Schnellmann, R. G. (2020). Regulation of mitochondrial dynamics and energetics in the diabetic renal proximal tubule by the β-adrenergic receptor agonist formoterol. American journal of physiology. Renal physiology, 319(5), F773-F779.
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  Diabetes is a prevalent metabolic disease that contributes to ∼50% of all end-stage renal disease and has limited treatment options. We previously demonstrated that the β-adrenergic receptor agonist formoterol induced mitochondrial biogenesis and promoted recovery from acute kidney injury. Here, we assessed the effects of formoterol on mitochondrial dysfunction and dynamics in renal proximal tubule cells (RPTCs) treated with high glucose and in a mouse model of type 2 diabetes. RPTCs exposed to 17 mM glucose exhibited increased electron transport chain (ETC) complex I, II, III, and V protein levels and reduced ATP levels and uncoupled oxygen consumption rate compared with RPTCs cultured in the absence of glucose or osmotic controls after 96 h. ETC proteins, ATP, and oxygen consumption rate were restored in RPTCs treated with formoterol. RPTCs exposed to high glucose had increased phospho-dynamin-related protein 1 (Drp1), a mitochondrial fission protein, and decreased mitofusin 1 (Mfn1), a mitochondrial fusion protein. Formoterol treatment restored phospho-Drp1 and Mfn1 to control levels. / and nondiabetic (/m) mice (10 wk old) were treated with formoterol or vehicle for 3 wk and euthanized. / mice showed increased renal cortical ETC protein levels in complexes I, III, and V and decreased ATP; these changes were prevented by formoterol. Phospho-Drp1 was increased and Mfn1 was decreased in / mice, and formoterol restored both to control levels. Together, these findings demonstrate that hyperglycemic conditions in vivo and exposure of RPTCs to high glucose similarly alter mitochondrial bioenergetic and dynamics profiles and that treatment with formoterol can reverse these effects. Formoterol may be a promising strategy for treating early stages of diabetic kidney disease.
• Kliger, A. S., & Brosius III, F. C. (2020). Preserving Kidney Function Instead of Replacing It. Clin J Am Soc Nephrol, 15, 129-131.
• Kliger, A. S., Brosius, F. C., & , D. K. (2020). Preserving Kidney Function Instead of Replacing It. Clinical journal of the American Society of Nephrology : CJASN, 15(1), 129-131.
• Marx, N., Rydén, L., Brosius, F., Ceriello, A., Cheung, M., Cosentino, F., Green, J., Kellerer, M., Koob, S., Kosiborod, M., Nedungadi, P., Rodbard, H. W., Vandvik, P. O., Standl, E., & Schnell, O. (2020). Proceedings of the Guideline Workshop 2019: Strategies for the Optimization of Guideline Processes in Diabetes, Cardiovascular Diseases, and Kidney Diseases. Diabetes technology & therapeutics, 22(7), 546-552.
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  The Guideline Workshop 2019, held in October 2019 in Munich, Germany, had the purpose of facilitating discussion on strategies for optimization of guideline processes in diabetes among a group of representatives of renown national and international societies in the field of diabetes, cardiology, and nephrology. Results of this panel's discussions are presented in this article and comprise a variety of suggestions for improving the quality and usability of guidelines, as well as to accelerate the development and responsiveness of guidelines to newly published, relevant data from clinical trials such as cardiovascular outcome trials in diabetes mellitus. These include, but are not limited to, recommendations to optimize presentation of content in guidelines, use of the Grading of Recommendations Assessment, Development, and Evaluation approach to rating the quality of evidence to harmonize guidelines, and utilization of digital health technologies to accelerate, streamline, and optimize communication on relevant data and development of clinical guidelines and necessary updates, while reducing costs. Recognizing that achieving alignment in guideline development among various medical organizations will be a long-term process, representatives from cross-sectional medical organizations relevant to cardio/renal metabolic disease and experts in guideline methodology will work together in the future. Among other activities, it is planned to continue the activity and organize a Guideline Workshop in 2020.
• Tuttle, K., Brosius III, F., M, C. A., & ., e. .. (2020). SGLT2 Inhibition for CKD and Cardiovascular Disease in Type 2 Diabetes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation. . 2020 Oct 26.. Diabetes, Online ahead of print.
• Afshinnia, F., Nair, V., Lin, J., Rajendiran, T. M., Soni, T., Byun, J., Sharma, K., Fort, P. E., Gardner, T. W., Looker, H. C., Nelson, R. G., Brosius, F. C., Feldman, E. L., Michailidis, G., Kretzler, M., & Pennathur, S. (2019). Increased lipogenesis and impaired β-oxidation predict type 2 diabetic kidney disease progression in American Indians. JCI insight, 4(21).
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  BACKGROUNDIn this study, we identified the lipidomic predictors of early type 2 diabetic kidney disease (DKD) progression, which are currently undefined.METHODSThis longitudinal study included 92 American Indians with type 2 diabetes. Serum lipids (406 from 18 classes) were quantified using mass spectrometry from baseline samples when iothalamate-based glomerular filtration rate (GFR) was at least 90 mL/min. Affymetrix GeneChip Array was used to measure renal transcript expression. DKD progression was defined as at least 40% decline in GFR during follow-up.RESULTSParticipants had a mean age of 45 ± 9 years and median urine albumin/creatinine ratio of 43 (interquartile range 11-144). The 32 progressors had significantly higher relative abundance of polyunsaturated triacylglycerols (TAGs) and a lower abundance of C16-C20 acylcarnitines (ACs) (P < 0.001). In a Cox regression model, the main effect terms of unsaturated free fatty acids and phosphatidylethanolamines and the interaction terms of C16-C20 ACs and short-low-double-bond TAGs by categories of albuminuria independently predicted DKD progression. Renal expression of acetyl-CoA carboxylase-encoding gene (ACACA) correlated with serum diacylglycerols in the glomerular compartment (r = 0.36, and P = 0.006) and with low-double-bond TAGs in the tubulointerstitial compartment (r = 0.52, and P < 0.001).CONCLUSIONCollectively, the findings reveal a previously unrecognized link between lipid markers of impaired mitochondrial β-oxidation and enhanced lipogenesis and DKD progression in individuals with preserved GFR. Renal acetyl-CoA carboxylase activation accompanies these lipidomic changes and suggests that it may be the underlying mechanism linking lipid abnormalities to DKD progression.TRIAL REGISTRATIONClinicalTrials.gov, NCT00340678.FUNDINGNIH R24DK082841, K08DK106523, R03DK121941, P30DK089503, P30DK081943, and P30DK020572.
• Alam, M. L., Katz, R., Bellovich, K. A., Bhat, Z. Y., Brosius, F. C., de Boer, I. H., Gadegbeku, C. A., Gipson, D. S., Hawkins, J. J., Himmelfarb, J., Kestenbaum, B. R., Kretzler, M., Robinson-Cohen, C., Steigerwalt, S. P., Tuegel, C., & Bansal, N. (2019). Soluble ST2 and Galectin-3 and Progression of CKD. Kidney international reports, 4(1), 103-111.
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  Cardiac biomarkers soluble ST2 (sST2) and galectin-3 may reflect cardiac inflammation and fibrosis. It is plausible that these mechanisms may also contribute to the progression of kidney disease. We examined associations of sST2 and galectin-3 with kidney function decline in participants with chronic kidney disease (CKD).
• Dieter, B. P., Meek, R. L., Anderberg, R. J., Cooney, S. K., Bergin, J. L., Zhang, H., Nair, V., Kretzler, M., Brosius, F. C., & Tuttle, K. R. (2019). Serum amyloid A and Janus kinase 2 in a mouse model of diabetic kidney disease. PloS one, 14(2), e0211555.
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  Serum amyloid A (SAA), a potent inflammatory mediator, and Janus kinase 2 (JAK2), an intracellular signaling kinase, are increased by diabetes. The aims were to elucidate: 1) a JAK2-mediated pathway for increased SAA in the kidneys of diabetic mice; 2) a JAK2-SAA pathway for inflammation in podocytes.
• Hinder, L. M., Sas, K. M., O'Brien, P. D., Backus, C., Kayampilly, P., Hayes, J. M., Lin, C. M., Zhang, H., Shanmugam, S., Rumora, A. E., Abcouwer, S. F., Brosius, F. C., Pennathur, S., & Feldman, E. L. (2019). Mitochondrial uncoupling has no effect on microvascular complications in type 2 diabetes. Scientific reports, 9(1), 881.
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  Diabetic peripheral neuropathy (DPN), diabetic kidney disease (DKD), and diabetic retinopathy (DR) contribute to significant morbidity and mortality in diabetes patients. The incidence of these complications is increasing with the diabetes epidemic, and current therapies minimally impact their pathogenesis in type 2 diabetes (T2D). Improved mechanistic understanding of each of the diabetic complications is needed in order to develop disease-modifying treatments for patients. We recently identified fundamental differences in mitochondrial responses of peripheral nerve, kidney, and retinal tissues to T2D in BKS-db/db mice. However, whether these mitochondrial adaptations are the cause or consequence of tissue dysfunction remains unclear. In the current study BKS-db/db mice were treated with the mitochondrial uncoupler, niclosamide ethanolamine (NEN), to determine the effects of mitochondrial uncoupling therapy on T2D, and the pathogenesis of DPN, DKD and DR. Here we report that NEN treatment from 6-24 wk of age had little effect on the development of T2D and diabetic complications. Our data suggest that globally targeting mitochondria with an uncoupling agent is unlikely to provide therapeutic benefit for DPN, DKD, or DR in T2D. These data also highlight the need for further insights into the role of tissue-specific metabolic reprogramming in the pathogenesis of diabetic complications.
• Brosius, F. C., & Ju, W. (2018). The Promise of Systems Biology for Diabetic Kidney Disease. Advances in chronic kidney disease, 25(2), 202-213.
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  Diabetic kidney disease (DKD) has a complex and prolonged pathogenesis involving many cell types in the kidney as well as extrarenal factors. It is clinically silent for many years after the onset of diabetes and usually progresses over decades. Given this complexity, a comprehensive and unbiased molecular approach is best suited to help identify the most critical mechanisms responsible for progression of DKD and those most suited for targeted intervention. Systems biological investigations provide such an approach since they examine the entire network of molecular changes that occur in a disease process in a comprehensive way instead of focusing on a single abnormal molecule or pathway. Systems biological studies can also start with analysis of the disease in humans, not in animal or cell culture models that often poorly reproduce the changes in human DKD. Indeed, in the last decade, systems biological approaches have led to the identification of critical molecular abnormalities in DKD and have directly led to development of new biomarkers and potential treatments for DKD.
• Troost, J. P., Hawkins, J., Jenkins, D. R., Gipson, D. S., Kretzler, M., El Shamy, O., Bellovich, K., Perumal, K., Bhat, Z., Massengill, S., Steigerwalt, S., Pennathur, S., Brosius, F. C., Gadegbeku, C. A., & , M. O. (2018). Consent for Genetic Biobanking in a Diverse Multisite CKD Cohort. Kidney international reports, 3(6), 1267-1275.
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  The goal of this study was to examine patterns in the likelihood of consent to genetic research among participants in a prospective kidney disease cohort and biobank, and to determine demographic, clinical, and socioeconomic factors linked to consent for ongoing and future genetic research.
• Tuegel, C., Katz, R., Alam, M., Bhat, Z., Bellovich, K., de Boer, I., Brosius, F., Gadegbeku, C., Gipson, D., Hawkins, J., Himmelfarb, J., Ju, W., Kestenbaum, B., Kretzler, M., Robinson-Cohen, C., Steigerwalt, S., & Bansal, N. (2018). GDF-15, Galectin 3, Soluble ST2, and Risk of Mortality and Cardiovascular Events in CKD. American journal of kidney diseases : the official journal of the National Kidney Foundation, 72(4), 519-528.
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  Inflammation, cardiac remodeling, and fibrosis may explain in part the excess risk for cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Growth differentiation factor 15 (GDF-15), galectin 3 (Gal-3), and soluble ST2 (sST2) are possible biomarkers of these pathways in patients with CKD.
• Tuttle, K. R., Brosius, F. C., Adler, S. G., Kretzler, M., Mehta, R. L., Tumlin, J. A., Tanaka, Y., Haneda, M., Liu, J., Silk, M. E., Cardillo, T. E., Duffin, K. L., Haas, J. V., Macias, W. L., Nunes, F. P., & Janes, J. M. (2018). JAK1/JAK2 inhibition by baricitinib in diabetic kidney disease: results from a Phase 2 randomized controlled clinical trial. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 33(11), 1950-1959.
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  Inflammation signaled by Janus kinases (JAKs) promotes progression of diabetic kidney disease (DKD). Baricitinib is an oral, reversible, selective inhibitor of JAK1 and JAK2. This study tested the efficacy of baricitinib versus placebo on albuminuria in adults with Type 2 diabetes at high risk for progressive DKD.
• Zeng, L., Mathew, A. V., Byun, J., Atkins, K. B., Brosius, F. C., & Pennathur, S. (2018). Myeloperoxidase-derived oxidants damage artery wall proteins in an animal model of chronic kidney disease-accelerated atherosclerosis. The Journal of biological chemistry, 293(19), 7238-7249.
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  Increased myeloperoxidase (MPO) levels and activity are associated with increased cardiovascular risk among individuals with chronic kidney disease (CKD). However, a lack of good animal models for examining the presence and catalytic activity of MPO in vascular lesions has impeded mechanistic studies into CKD-associated cardiovascular diseases. Here, we show for the first time that exaggerated atherosclerosis in a pathophysiologically relevant CKD mouse model is associated with increased macrophage-derived MPO activity. Male 7-week-old LDL receptor-deficient mice underwent sham (control mice) or 5/6 nephrectomy and were fed either a low-fat or high-fat, high-cholesterol diet for 24 weeks, and the extents of atherosclerosis and vascular reactivity were assessed. MPO expression and oxidation products-protein-bound oxidized tyrosine moieties 3-chlorotyrosine, 3-nitrotyrosine, and 'dityrosine-were examined with immunoassays and confirmed with mass spectrometry (MS). As anticipated, the CKD mice had significantly higher plasma creatinine, urea nitrogen, and intact parathyroid hormone along with lower hematocrit and body weight. On both the diet regimens, CKD mice did not have hypertension but had lower cholesterol and triglyceride levels than the control mice. Despite the lower cholesterol levels, CKD mice had increased aortic plaque areas, fibrosis, and luminal narrowing. They also exhibited increased MPO expression and activity ( increased oxidized tyrosines) that co-localized with infiltrating lesional macrophages and diminished vascular reactivity. In summary, unlike non-CKD mouse models of atherosclerosis, CKD mice exhibit increased MPO expression and catalytic activity in atherosclerotic lesions, which co-localize with lesional macrophages. These results implicate macrophage-derived MPO in CKD-accelerated atherosclerosis.
• Hinder, L. M., Park, M., Rumora, A. E., Hur, J., Eichinger, F., Pennathur, S., Kretzler, M., Brosius, F. C., & Feldman, E. L. (2017). Comparative RNA-Seq transcriptome analyses reveal distinct metabolic pathways in diabetic nerve and kidney disease. Journal of cellular and molecular medicine, 21(9), 2140-2152.
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  Treating insulin resistance with pioglitazone normalizes renal function and improves small nerve fibre function and architecture; however, it does not affect large myelinated nerve fibre function in mouse models of type 2 diabetes (T2DM), indicating that pioglitazone affects the body in a tissue-specific manner. To identify distinct molecular pathways regulating diabetic peripheral neuropathy (DPN) and nephropathy (DN), as well those affected by pioglitazone, we assessed DPN and DN gene transcript expression in control and diabetic mice with or without pioglitazone treatment. Differential expression analysis and self-organizing maps were then used in parallel to analyse transcriptome data. Differential expression analysis showed that gene expression promoting cell death and the inflammatory response was reversed in the kidney glomeruli but unchanged or exacerbated in sciatic nerve by pioglitazone. Self-organizing map analysis revealed that mitochondrial dysfunction was normalized in kidney and nerve by treatment; however, conserved pathways were opposite in their directionality of regulation. Collectively, our data suggest inflammation may drive large fibre dysfunction, while mitochondrial dysfunction may drive small fibre dysfunction in T2DM. Moreover, targeting both of these pathways is likely to improve DN. This study supports growing evidence that systemic metabolic changes in T2DM are associated with distinct tissue-specific metabolic reprogramming in kidney and nerve and that these changes play a critical role in DN and small fibre DPN pathogenesis. These data also highlight the potential dangers of a 'one size fits all' approach to T2DM therapeutics, as the same drug may simultaneously alleviate one complication while exacerbating another.
• Korte, E. A., Caster, D. J., Barati, M. T., Tan, M., Zheng, S., Berthier, C. C., Brosius, F. C., Vieyra, M. B., Sheehan, R. M., Kosiewicz, M., Wysoczynski, M., Gaffney, P. M., Salant, D. J., McLeish, K. R., & Powell, D. W. (2017). ABIN1 Determines Severity of Glomerulonephritis via Activation of Intrinsic Glomerular Inflammation. The American journal of pathology, 187(12), 2799-2810.
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  Transcription factor NF-κB regulates expression of numerous genes that control inflammation and is activated in glomerular cells in glomerulonephritis (GN). We previously identified genetic variants for a NF-κB regulatory, ubiquitin-binding protein ABIN1 as risk factors for GN in systemic autoimmunity. The goal was to define glomerular inflammatory events controlled by ABIN1 function in GN. Nephrotoxic serum nephritis was induced in wild-type (WT) and ubiquitin-binding deficient ABIN1[D485N] mice, and renal pathophysiology and glomerular inflammatory phenotypes were assessed. Proteinuria was also measured in ABIN1[D485N] mice transplanted with WT mouse bone marrow. Inflammatory activation of ABIN1[D472N] (D485N homolog) cultured human-derived podocytes, and interaction with primary human neutrophils were also assessed. Disruption of ABIN1 function exacerbated proteinuria, podocyte injury, glomerular NF-κB activity, glomerular expression of inflammatory mediators, and glomerular recruitment and retention of neutrophils in antibody-mediated nephritis. Transplantation of WT bone marrow did not prevent the increased proteinuria in ABIN1[D845N] mice. Tumor necrosis factor-stimulated enhanced expression and secretion of NF-κB-targeted proinflammatory mediators in ABIN1[D472N] cultured podocytes compared with WT cells. Supernatants from ABIN1[D472N] podocytes accelerated chemotaxis of human neutrophils, and ABIN1[D472N] podocytes displayed a greater susceptibility to injurious morphologic findings induced by neutrophil granule contents. These studies define a novel role for ABIN1 dysfunction and NF-κB in mediating GN through proinflammatory activation of podocytes.
• Nair, V., Robinson-Cohen, C., Smith, M. R., Bellovich, K. A., Bhat, Z. Y., Bobadilla, M., Brosius, F., de Boer, I. H., Essioux, L., Formentini, I., Gadegbeku, C. A., Gipson, D., Hawkins, J., Himmelfarb, J., Kestenbaum, B., Kretzler, M., Magnone, M. C., Perumal, K., Steigerwalt, S., , Ju, W., et al. (2017). Growth Differentiation Factor-15 and Risk of CKD Progression. Journal of the American Society of Nephrology : JASN, 28(7), 2233-2240.
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  Growth differentiation factor-15 (GDF-15) is a member of the TGF-β cytokine superfamily that is widely expressed and may be induced in response to tissue injury. Elevations in GDF-15 may identify a novel pathway involved in loss of kidney function among patients with CKD. Among participants in the Clinical Phenotyping and Resource Biobank (C-PROBE) study and the Seattle Kidney Study (SKS), we tested whether kidney tissue expression of GDF15 mRNA correlates with circulating levels of GDF-15 and whether elevations in circulating GDF-15 are associated with decline in kidney function. In matching samples of 24 patients with CKD from the C-PROBE study, circulating GDF-15 levels significantly correlated with intrarenal GDF15 transcript levels (r=0.54, P=0.01). Among the 224 C-PROBE and 297 SKS participants, 72 (32.1%) and 94 (32.0%) patients, respectively, reached a composite end point of 30% decline in eGFR or progression to ESRD over a median of 1.8 and 2.0 years of follow up, respectively. In multivariable models, after adjusting for potential confounders, every doubling of GDF-15 level associated with a 72% higher (95% confidence interval, 1.21 to 4.45; P=0.003) and 65% higher (95% confidence interval, 1.08 to 2.50; P=0.02) risk of progression of kidney disease in C-PROBE and SKS participants, respectively. These results show that circulating GDF-15 levels strongly correlated with intrarenal expression of GDF15 and significantly associated with increased risk of CKD progression in two independent cohorts. Circulating GDF-15 may be a marker for intrarenal GDF15-related signaling pathways associated with CKD and CKD progression.
• O'Brien, P. D., Hinder, L. M., Parlee, S. D., Hayes, J. M., Backus, C., Zhang, H., Ma, L., Sakowski, S. A., Brosius, F. C., & Feldman, E. L. (2017). Dual CCR2/CCR5 antagonist treatment attenuates adipose inflammation, but not microvascular complications in ob/ob mice. Diabetes, obesity & metabolism, 19(10), 1468-1472.
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  Diabetic peripheral neuropathy (DPN) and diabetic kidney disease (DKD) are common diabetic complications with limited treatment options. Experimental studies show that targeting inflammation using chemokine receptor (CCR) antagonists ameliorates DKD, presumably by reducing macrophage accumulation or activation. As inflammation is implicated in DPN development, we assessed whether CCR2 and CCR5 antagonism could also benefit DPN. Five-week-old ob/ob mice were fed a diet containing MK-0812, a dual CCR2-CCR5 receptor antagonist, for 8 weeks; DPN, DKD and metabolic phenotyping were then performed to determine the effect of CCR inhibition. Although MK-0812 reduced macrophage accumulation in adipose tissue, the treatment had largely no effect on metabolic parameters, nerve function or kidney disease in ob/ob mice. These results conflict with published data that demonstrate a benefit of CCR antagonists for DKD and hyperglycaemia. We conclude that CCR signaling blockade is ineffective in ob/ob mice and suspect that this is explained by the severe hyperglycaemia found in this model. It remains to be determined whether MK-0812 treatment, alone or in combination with improved glycaemic control, is useful in preventing diabetic complications in alternate animal models.
• Sas, K. M., Lin, J., Rajendiran, T. M., Soni, T., Nair, V., Hinder, L. M., Jagadish, H. V., Gardner, T. W., Abcouwer, S. F., Brosius, F. C., Feldman, E. L., Kretzler, M., Michailidis, G., & Pennathur, S. (2017). Shared and distinct lipid-lipid interactions in plasma and affected tissues in a diabetic mouse model. Journal of lipid research.
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  Lipids are ubiquitous metabolites with diverse functions; abnormalities in lipid metabolism appear related to complications from multiple diseases, including type 2 diabetes. Through technological advances, the entire lipidome has been characterized, and researchers now need computational approaches to better understand lipid network perturbations in different diseases. Using a mouse model of type 2 diabetes with microvascular complications, we examined lipid levels in plasma and in renal, neural, and retinal tissues to identify shared and distinct lipid abnormalities. We used correlation analysis to construct interaction networks in each tissue, to associate changes in lipids with changes in enzymes of lipid metabolism, and to identify overlap of co-regulated lipid subclasses between plasma and each tissue to define subclasses of plasma lipids to use as surrogates of tissue lipid metabolism. Lipid metabolism alterations were mostly tissue specific in the kidney, nerve and retina; no lipid changes correlated between the plasma and all three tissue types. However, alterations in diacylglycerol and in lipids containing arachidonic acid, an inflammatory mediator, were shared among the tissue types, and the highly saturated cholesterol esters were similarly co-regulated between plasma and each tissue type in the diabetic mouse. Our results identified several patterns of altered lipid metabolism that may help identify pathogenic alterations in different issues and could be used as biomarkers in future research into diabetic microvascular tissue damage.
• Zhang, H., Nair, V., Saha, J., Atkins, K. B., Hodgin, J. B., Saunders, T. L., Myers, M. G., Werner, T., Kretzler, M., & Brosius, F. C. (2017). Podocyte-specific JAK2 overexpression worsens diabetic kidney disease in mice. Kidney international, 92(4), 909-921.
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  Activation of JAK-STAT signaling has been implicated in the pathogenesis of diabetic kidney disease. An increased expression of JAK-STAT genes was found in kidney glomerular cells, including podocytes, in patients with early diabetic kidney disease. However, it is not known whether increased expression of JAK or STAT isoforms in glomerular cells can lead to worsening nephropathy in the setting of diabetes. Therefore, we overexpressed JAK2 mRNA specifically in glomerular podocytes of 129S6 mice to determine whether this change alone could worsen diabetic kidney disease. A 2-3 fold increase in glomerular JAK2 expression, an increase similar to that found in humans with early diabetic kidney disease, led to substantial and statistically significant increases in albuminuria, mesangial expansion, glomerulosclerosis, glomerular fibronectin accumulation, and glomerular basement membrane thickening, and a significant reduction in podocyte density in diabetic mice. Treatment with a specific JAK1/2 inhibitor for 2 weeks partly reversed the major phenotypic changes of diabetic kidney disease and specifically normalized expression of a number of downstream STAT3-dependent genes implicated in diabetic kidney disease progression. Thus, moderate increases in podocyte JAK2 expression at levels similar to those in patients with early diabetic kidney disease can lead directly to phenotypic and other alterations of progressive diabetic glomerulopathy. Hence, inhibition of these changes by treatment with a JAK1/2 inhibitor suggests that such treatment may help retard progression of early diabetic kidney disease in patients.

Presentations

• Brosius III, F. (2017, April). Diabetic Kidney Disease An Inflammatory Disease. World Congress of Nephrology. Mexico City, Mexico: International Society of Nephrology.
• Brosius III, F. (2017, January). New approaches to the treatment of diabetic kidney disease. 4th Japan Kidney Conference. Tokyo, Japan.
• Brosius III, F. (2017, October). New fighters against diabetic nephropathy; a rogue one disease. D.E.V.E.N.I.R. Foundation Annual Meeting. Montreal, Quebec, Canada: D.E.V.E.N.I.R. Foundation.