Causal connections between axon guidance proteins and early progressive kidney function decline in diabetes

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PROJECT SUMMARY/ABSTRACT End stage kidney disease (ESKD) due to diabetes continues to rise despite improvements in glycemic control and widespread treatment with reno-protective drugs. A more complete understanding of the mechanisms responsible for the progressive decline in kidney function is urgently needed to identify new, more efficacious methods of treatment and prevention of ESKD in diabetes. By studying diabetic patients with advanced kidney disease with proteinuria and CKD≥3, we obtained two novel findings related to progression to ESKD in both T1D and T2D. Using follow-up data from two independent cohorts and global miRNAs platform, we found a specific profile of plasma miRNAs strongly associated with progression to ESKD. These miRNAs specifically targeted axon guidance pathway (AGP) proteins. Strikingly, circulating levels of 6 AGP proteins (two ligands EFNA4, EFN5 and 4 receptors EPHA2, EPHB2, EPHB6, UNC5C) were very strongly associated with the extent of kidney structural lesions in the T2D Pima Indian cohort and progression to ESKD in four independent cohorts. Our findings are the first to implicate circulating AGP proteins in the progression to ESKD in diabetes. To follow-up these findings, we propose a multi-disciplinary study to assess the role of the AGP proteins in the development of early progressive kidney functional decline (PKFD) and learn about mechanisms through which circulating AGP may damage the kidney. Three complementary studies are proposed. Dr. Krolewski’s lab will examine whether elevated levels of two exemplars of AGP proteins EFNA4 and EPHA2 are associated/causally related to the development of early PKFD. Dr. Kretzler’s lab will examine how circulating levels of the AGP proteins may impact candidate etiological pathways in kidney cells. Dr. Korstanje’s lab will examine whether genetic manipulation of circulating levels of EFNA4 and EPHA2 in mice models of diabetes lead to onset of diabetic kidney disease. The proposed research has the following specific aims: Aim #1: We will examine the effect of variation of circulating levels of the candidate miRNAs and AGP proteins examined at baseline in the two nested cases-control studies of T1D patients with Normo-Alb (n=390) and Micro- Alb (n=430) on risk of early PKFD during 7-15 years of follow-up. Aim #2: We will examine the link between circulating levels of the candidate AGP proteins and dysregulation of candidate etiological pathways using single cell RNA sequencing results obtained from research kidney biopsies from Pima Indians with T2D. Aim #3: We will test EPHA2 and EFNA4 for their ability to modify renal phenotypes in a diabetic mouse model and test whether miR-328-5p and miR-339-5p, which are both downregulated during progression to ESKD and have orthologs in the mouse, can affect the impact of these AGP proteins on diabetic kidney disease. The proposed research has a very high probability of generating novel findings. Its success is assured by the fact that the co-investigators have a track record of collaboration, and study cohorts and biobanks of specimens from all members of the Joslin Kidney Study and Pima Indian Kidney Study are available.