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Acute kidney injury (AKI) occurs in approximately 13% of hospitalized patients and predisposes patients to chronic kidney disease (CKD) through the AKI-to-CKD transition. Studies from our laboratory and others have demonstrated that maladaptive repair of proximal tubule cells (PTCs), including induction of dedifferentiation, G2/M cell cycle arrest, senescence, and profibrotic cytokine secretion, is a key process promoting AKI-to-CKD transition, kidney fibrosis, and CKD progression. The molecular mechanisms governing maladaptive repair and the relative contribution of dedifferentiation, G2/M arrest, and senescence to CKD remain to be resolved. We identified cyclin G1 (CG1) as a factor upregulated in chronically injured and maladaptively repaired PTCs. We demonstrated that global deletion of CG1 inhibits G2/M arrest and fibrosis. Pharmacological induction of G2/M arrest in CG1-knockout mice, however, did not fully reverse the antifibrotic phenotype. Knockout of CG1 did not alter dedifferentiation and proliferation in the adaptive repair response following AKI. Instead, CG1 specifically promoted the prolonged dedifferentiation of kidney tubule epithelial cells observed in CKD. Mechanistically, CG1 promotes dedifferentiation through activation of cyclin-dependent kinase 5 (CDK5). Deletion of CDK5 in kidney tubule cells did not prevent G2/M arrest but did inhibit dedifferentiation and fibrosis. Thus, CG1 and CDK5 represent a unique pathway that regulates maladaptive, but not adaptive, dedifferentiation, suggesting they could be therapeutic targets for CKD.

The mechanical properties of the extracellular matrix (ECM) are important in maintaining normal physiological function, and changes in ECM mechanics drive disease. The biochemical structure of the ECM is modified with aging and in diseases such as diabetes. One mechanism of ECM modification is the non-enzymatic reaction between sugars and ECM proteins resulting in formation of advanced glycation end products (AGEs). Some AGE reactions result in formation of molecular crosslinks within or between matrix proteins, but it is not clear how sugar-mediated biochemical modification of the ECM translates to changes in kidney ECM mechanical properties. AGE-mediated changes in ECM mechanics may have pathological consequences in diabetic kidney disease. To determine how sugars alter the mechanical properties of the kidney ECM, we employ custom methodologies to evaluate the mechanical properties of isolated tubular basement membrane (TBM) and glomerular ECM. Results show that the mechanical properties of TBM and glomerular ECM stiffness were altered by incubation in glucose and ribose. Mechanical behavior of TBM and glomerular ECM were further evaluated using mechanical models for hyperelastic materials in tension and compression. Increased ECM stiffness following sugar modification corresponded to increased crosslinking as determined by ECM fluorescence and reduced pepsin extractability of sugar modified ECM. These results show that sugar-induced modifications significantly affect the mechanical properties of kidney ECM. AGE-mediated changes in ECM mechanics may be important in progression of chronic diseases including diabetic kidney disease.