Myeloid-derived growth factor (MYDGF), mainly secreted by bone marrow-derived cells, has been known to promote glucagon-like peptide-1 production and improve glucose/lipid metabolism in mouse models of diabetes, but little is known about the functions of MYDGF in diabetic kidney disease (DKD). Here, we investigated whether MYDGF can prevent the progression of DKD.
In vivo experiments, both loss- and gain-of-function strategies were used to evaluate the effect of MYDGF on albuminuria and pathological glomerular lesions. We used streptozotocin-treated Mydgf knockout and wild-type mice on high fat diets to induce a model of DKD. Then, albuminuria, glomerular lesions and podocyte injury were evaluated in Mydgf knockout and wild-type DKD mice treated with adeno-associated virus-mediated Mydgf gene transfer. In vitro and ex vivo experiments, the expression of slit diaphragm protein nephrin and podocyte apoptosis were evaluated in conditionally immortalised mouse podocytes and isolated glomeruli from non-diabetic wild-type mice treated with recombinant MYDGF.
MYDGF deficiency caused more severe podocyte injury in DKD mice, including the disruption of slit diaphragm proteins (nephrin and podocin) and an increase in desmin expression and podocyte apoptosis, and subsequently caused more severe glomerular injury and increased albuminuria by 39.6% compared with those of wild-type DKD mice (p < 0.01). Inversely, MYDGF replenishment attenuated podocyte and glomerular injury in both wild-type and Mydgf knockout DKD mice and then decreased albuminuria by 36.7% in wild-type DKD mice (p < 0.01) and 34.9% in Mydgf knockout DKD mice (p < 0.01). Moreover, recombinant MYDGF preserved nephrin expression and inhibited podocyte apoptosis in vitro and ex vivo. Mechanistically, the renoprotection of MYDGF was attributed to the activation of the Akt/Bcl-2-associated death promoter (BAD) pathway.
The study demonstrates that MYDGF protects podocytes from injury and prevents the progression of DKD, providing a novel strategy for the treatment of DKD.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
All data generated or analysed during this study are included in this published article (and its supplementary information files).
Bcl-2-associated death promoter
B-cell lymphoma 2
Bone marrow-derived cell
Bone marrow mesenchymal stem cell
Bone marrow mononuclear cell
Bone marrow cell
Blood urea nitrogen
Diabetic kidney disease
Glomerular basement membrane
Myeloid-derived growth factor
Protein kinase A
p90 ribosomal S6 kinase
Small interfering RNA
p70 ribosomal S6 kinase
Transmission electron microscopy
Urinary albumin/creatinine ratio
Wilms’ tumour 1
Brosius FC, Tuttle KR, Kretzler M (2016) JAK inhibition in the treatment of diabetic kidney disease. Diabetologia 59(8):1624–1627. https://doi.org/10.1007/s00125-016-4021-5
Jefferson JA, Shankland SJ, Pichler RH (2008) Proteinuria in diabetic kidney disease: a mechanistic viewpoint. Kidney Int 74(1):22–36. https://doi.org/10.1038/ki.2008.128
Holderied A, Romoli S, Eberhard J et al (2015) Glomerular parietal epithelial cell activation induces collagen secretion and thickening of Bowman’s capsule in diabetes. Lab Investig 95(3):273–282. https://doi.org/10.1038/labinvest.2014.160
Gruden G, Perin PC, Camussi G (2005) Insight on the pathogenesis of diabetic nephropathy from the study of podocyte and mesangial cell biology. Curr Diabetes Rev 1(1):27–40. https://doi.org/10.2174/1573399052952622
Susztak K, Raff AC, Schiffer M, Bottinger EP (2006) Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes 55(1):225–233. https://doi.org/10.2337/diabetes.55.1.225
Li JJ, Kwak SJ, Jung DS et al (2007) Podocyte biology in diabetic nephropathy. Kidney Int Suppl 106:S36–S42. https://doi.org/10.1038/sj.ki.5002384
Zhan H, Jin J, Liang S, Zhao L, Gong J, He Q (2019) Tripterygium glycoside protects diabetic kidney disease mouse serum-induced podocyte injury by upregulating autophagy and downregulating β-arrestin-1. Histol Histopathol 34(8):943–952. https://doi.org/10.14670/HH-18-097
Golle L, Gerth HU, Beul K et al (2017) Bone marrow-derived cells and their conditioned medium induce microvascular repair in uremic rats by stimulation of endogenous repair mechanisms. Sci Rep 7(1):9444. https://doi.org/10.1038/s41598-017-09883-x
Zhang Y, Yuen DA, Advani A et al (2012) Early-outgrowth bone marrow cells attenuate renal injury and dysfunction via an antioxidant effect in a mouse model of type 2 diabetes. Diabetes 61(8):2114–2125. https://doi.org/10.2337/db11-1365
Hamza AH, Al-Bishri WM, Damiati LA, Ahmed HH (2017) Mesenchymal stem cells: a future experimental exploration for recession of diabetic nephropathy. Ren Fail 39(1):67–76. https://doi.org/10.1080/0886022x.2016.1244080
Abdel Aziz MT, Wassef MA, Ahmed HH et al (2014) The role of bone marrow derived-mesenchymal stem cells in attenuation of kidney function in rats with diabetic nephropathy. Diabetol Metab Syndr 6(1):34. https://doi.org/10.1186/1758-5996-6-34
Castiglione RC, Maron-Gutierrez T, Barbosa CM et al (2013) Bone marrow-derived mononuclear cells promote improvement in glomerular function in rats with early diabetic nephropathy. Cell Physiol Biochem 32(3):699–718. https://doi.org/10.1159/000354473
Packham DK, Fraser IR, Kerr PG, Segal KR (2016) Allogeneic mesenchymal precursor cells (MPC) in diabetic nephropathy: a randomized, placebo-controlled, dose escalation study. E Bio Medicine 12:263–269. https://doi.org/10.1016/j.ebiom.2016.09.011
Gaipov A, Taubaldiyeva Z, Askarov M et al (2019) Infusion of autologous bone marrow derived mononuclear stem cells potentially reduces urinary markers in diabetic nephropathy. J Nephrol 32(1):65–73. https://doi.org/10.1007/s40620-018-0548-5
Li H, Rong P, Ma X et al (2018) Paracrine effect of mesenchymal stem cell as a novel therapeutic strategy for diabetic nephropathy. Life Sci 215:113–118. https://doi.org/10.1016/j.lfs.2018.11.001
Nagaishi K, Mizue Y, Chikenji T et al (2016) Mesenchymal stem cell therapy ameliorates diabetic nephropathy via the paracrine effect of renal trophic factors including exosomes. Sci Rep 6:34842. https://doi.org/10.1038/srep34842
Korf-Klingebiel M, Reboll MR, Klede S et al (2015) Myeloid-derived growth factor (C19orf10) mediates cardiac repair following myocardial infarction. Nat Med 21(2):140–149. https://doi.org/10.1038/nm.3778
Wang L, Li Y, Guo B et al (2020) Myeloid-derived growth factor promotes intestinal glucagon-like peptide-1 production in male mice with type 2 diabetes. Endocrinology 161(2). https://doi.org/10.1210/endocr/bqaa003
Du P, Fan B, Han H et al (2013) NOD2 promotes renal injury by exacerbating inflammation and podocyte insulin resistance in diabetic nephropathy. Kidney Int 84(2):265–276. https://doi.org/10.1038/ki.2013.113
Liu M, Liang K, Zhen J et al (2017) Sirt6 deficiency exacerbates podocyte injury and proteinuria through targeting Notch signaling. Nat Commun 8(1):413. https://doi.org/10.1038/s41467-017-00498-4
Li H, Li Y, Xiang L et al (2017) GDF11 attenuates development of type 2 diabetes via improvement of islet β-cell function and survival. Diabetes 66(7):1914–1927. https://doi.org/10.2337/db17-0086
Mei W, Xiang G, Li Y et al (2016) GDF11 protects against endothelial injury and reduces atherosclerotic lesion formation in apolipoprotein E-null mice. Mol Ther 24(11):1926–1938. https://doi.org/10.1038/mt.2016.160
Zhang J, Li Y, Li H et al (2018) GDF11 improves angiogenic function of EPCs in diabetic limb ischemia. Diabetes 67(10):2084–2095. https://doi.org/10.2337/db17-1583
Gusella GL, Fedorova E, Hanss B, Marras D, Klotman ME, Klotman PE (2002) Lentiviral gene transduction of kidney. Hum Gene Ther 13(3):407–414. https://doi.org/10.1089/10430340252792530
Liu J, Feng X, Tian Y et al (2019) Knockdown of TRIM27 expression suppresses the dysfunction of mesangial cells in lupus nephritis by FoxO1 pathway. J Cell Physiol 234(7):11555–11566. https://doi.org/10.1002/jcp.27810
Bao H, Ge Y, Peng A, Gong R (2015) Fine-tuning of NFκB by glycogen synthase kinase 3β directs the fate of glomerular podocytes upon injury. Kidney Int 87(6):1176–1190. https://doi.org/10.1038/ki.2014.428
van den Berg JG, van den Bergh Weerman MA, Assmann KJ, Weening JJ, Florquin S (2004) Podocyte foot process effacement is not correlated with the level of proteinuria in human glomerulopathies. Kidney Int 66(5):1901–1906. https://doi.org/10.1111/j.1523-1755.2004.00964.x
Zhu B, Li Y, Mei W et al (2019) Alogliptin improves endothelial function by promoting autophagy in perivascular adipose tissue of obese mice through a GLP-1-dependent mechanism. Vasc Pharmacol 115:55–63. https://doi.org/10.1016/j.vph.2018.11.003
Ding Y, Jiang H, Meng B, Zhu B, Yu X, Xiang G (2019) Sweroside-mediated mTORC1 hyperactivation in bone marrow mesenchymal stem cells promotes osteogenic differentiation. J Cell Biochem 120(9):16025–16036. https://doi.org/10.1002/jcb.28882
Alicic RZ, Rooney MT, Tuttle KR (2017) Diabetic kidney disease: challenges, progress, and possibilities. Clin J Am Soc Nephrol 12(12):2032–2045. https://doi.org/10.2215/CJN.11491116
Horne SJ, Vasquez JM, Guo Y et al (2018) Podocyte-specific loss of Krüppel-like factor 6 increases mitochondrial injury in diabetic kidney disease. Diabetes 67(11):2420–2433. https://doi.org/10.2337/db17-0958
Yu SY, Qi R (2013) Role of BAD in podocyte apoptosis induced by puromycin aminonucleoside. Transplant Proc 45(2):569–573. https://doi.org/10.1016/j.transproceed.2012.07.160
Bridgewater DJ, Ho J, Sauro V, Matsell DG (2005) Insulin-like growth factors inhibit podocyte apoptosis through the PI3 kinase pathway. Kidney Int 67(4):1308–1314. https://doi.org/10.1111/j.1523-1755.2005.00208.x
Kang Y, Li Y, Zhang T, Chi Y, Liu M (2019) Effects of transcription factor EB on oxidative stress and apoptosis induced by high glucose in podocytes. Int J Mol Med 44(2):447–456. https://doi.org/10.3892/ijmm.2019.4209
Oh J, Beckmann J, Bloch J et al (2011) Stimulation of the calcium-sensing receptor stabilizes the podocyte cytoskeleton, improves cell survival, and reduces toxin-induced glomerulosclerosis. Kidney Int 80(5):483–492. https://doi.org/10.1038/ki.2011.105
Harada H, Becknell B, Wilm M et al (1999) Phosphorylation and inactivation of BAD by mitochondria-anchored protein kinase A. Mol Cell 3(4):413–422. https://doi.org/10.1016/s1097-2765(00)80469-4
Datta SR, Dudek H, Tao X et al (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91(2):231–241. https://doi.org/10.1016/s0092-8674(00)80405-5
Chandrasekher G, Sailaja D (2004) Phosphatidylinositol 3-kinase (PI-3K)/Akt but not PI-3K/p70 S6 kinase signaling mediates IGF-1-promoted lens epithelial cell survival. Invest Ophthalmol Vis Sci 45(10):3577–3588. https://doi.org/10.1167/iovs.04-0279
Mogensen CE (1971) Glomerular filtration rate and renal plasma flow in short-term and long-term juvenile diabetes mellitus. Scand J Clin Lab Invest 28(1):91–100. https://doi.org/10.3109/00365517109090667
Katsoulieris EN, Drossopoulou GI, Kotsopoulou ES, Vlahakos DV, Lianos EA, Tsilibary EC (2016) High glucose impairs insulin signaling in the glomerulus: an in vitro and ex vivo approach. PLoS One 11(7):e0158873. https://doi.org/10.1371/journal.pone.0158873
Song Z, Guo Y, Zhou M, Zhang X (2014) The PI3K/p-Akt signaling pathway participates in calcitriol ameliorating podocyte injury in DN rats. Metabolism 63(10):1324–1333. https://doi.org/10.1016/j.metabol.2014.06.013
Anil Kumar P, Welsh GI, Saleem MA, Menon RK (2014) Molecular and cellular events mediating glomerular podocyte dysfunction and depletion in diabetes mellitus. Front Endocrinol (Lausanne) 5:151. https://doi.org/10.3389/fendo.2014.00151
Barutta F, Grimaldi S, Franco I et al (2014) Deficiency of cannabinoid receptor of type 2 worsens renal functional and structural abnormalities in streptozotocin-induced diabetic mice. Kidney Int 86(5):979–990. https://doi.org/10.1038/ki.2014.165
Dai C, Saleem MA, Holzman LB, Mathieson P, Liu Y (2010) Hepatocyte growth factor signaling ameliorates podocyte injury and proteinuria. Kidney Int 77(11):962–973. https://doi.org/10.1038/ki.2010.40
Wang XM, Yao M, Liu SX, Hao J, Liu QJ, Gao F (2014) Interplay between the Notch and PI3K/Akt pathways in high glucose-induced podocyte apoptosis. Am J Physiol Renal Physiol 306(2):F205–F213. https://doi.org/10.1152/ajprenal.90005.2013
Huber TB, Hartleben B, Kim J et al (2003) Nephrin and CD2AP associate with phosphoinositide 3-OH kinase and stimulate AKT-dependent signaling. Mol Cell Biol 23(14):4917–4928. https://doi.org/10.1128/mcb.23.14.4917-4928.2003
Fujita H, Morii T, Fujishima H et al (2014) The protective roles of GLP-1R signaling in diabetic nephropathy: possible mechanism and therapeutic potential. Kidney Int 85(3):579–589. https://doi.org/10.1038/ki.2013.427
Mann JFE, Ørsted DD, Brown-Frandsen K et al (2017) Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med 377(9):839–848. https://doi.org/10.1056/NEJMoa1616011
Bortnov V, Annis DS, Fogerty FJ, Barretto KT, Turton KB, Mosher DF (2018) Myeloid-derived growth factor is a resident endoplasmic reticulum protein. J Biol Chem 293(34):13166–13175. https://doi.org/10.1074/jbc.ac118.002052
Authors’ relationships and activities
The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.
This work was supported by grants from the National Natural Science Foundation of China (NSFC 81870573, 81370896, 81570730), National Key Research and Development Program of China (2016YFC1305601) and Research Project of Health Commission of Hubei Province (WJ2017H0031).
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
About this article
Cite this article
He, M., Li, Y., Wang, L. et al. MYDGF attenuates podocyte injury and proteinuria by activating Akt/BAD signal pathway in mice with diabetic kidney disease. Diabetologia (2020). https://doi.org/10.1007/s00125-020-05197-2
- Diabetic kidney disease
- Myeloid-derived growth factor
- Podocyte injury