Finerenone Prevents Kidney Damage by Stem Cell Mobilization Through SDF-1α /CXCR4 Axis Upregulation in Type 1 Diabetic Rats with CKD

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Background: Finerenone (FIN), a non-steroidal mineralocorticoid receptor antagonist, has shown a protective effect on kidney and cardiovascular damage progression in type 1 diabetic (DM1) Munich Wistar Frömter (MWF) rats with established chronic kidney disease (CKD). We now hypothesize that protection is associated to stromal cell-derived factor 1 α (SDF-1α)/CXCR4 chemokine axis activation, which is critical in tissue repair and stem cell mobilization. Methods: DM1 was induced in sixteen-week-old MWF by streptozotocin injection (15 mg/Kg, i.p.) together with exposure to a high fat/high sucrose (HF/HS) diet for 6 weeks (MWF-D). The MWF-D-FIN group was additionally treated with 10 mg/Kg/day of FIN included in the HF/HS diet. Non-diabetic MWF were used as a control (n = 6/group). We analysed renal histology, gene expression RT-qPCR, protein levels by Western blot or ELISA, and matrix metalloproteinases (MMP)-2 and MMP-9 activities by zymography. Results: Kidneys of MWF-D exhibited increased glomerulosclerosis, interstitial inflammation, tubular necrosis and collagen I content along with an upregulation of MMP-2 and MMP-9 activities. These alterations were reduced by FIN treatment. No differences between groups were observed for Timp-1, Timp-2 and Pai-1 gene mRNA expression, or and for TIMP-1 and TIMP-2 protein levels. CXCR4 and its ligand SDF-1α, which are key for stem cell migration, were elevated in MWF-D rats and further increased by FIN treatment. SDF-1α is cleaved by MMP-2 and MMP-9 to a truncated SDF-1α (5-67), which does not bind CXCR4, but CXCR3. Interestingly, SDF-1α (5-67) was significantly reduced by FIN, without differences in CXCR3. Kidney slices of MWF-D-FIN showed higher immunofluorescence and colocalization of CXCR4 and CD34, a marker of hematopoietic stem cells. Conclusion: FIN prevents the progression of kidney damage in diabetic MWF due to a reduction of MMP-2 and MMP-9 activities. This leads to an upregulation of the SDF-1α /CXCR4 axis and to an increase in hematopoietic stem cell migration to the kidney and histomorphological repair. Funding: Government Support – Non-U.S.

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