Progressive kidney diseases are often associated with scarring of the kidney’s filtration unit, a condition called focal segmental glomerulosclerosis (FSGS). This scarring is due to loss of podocytes, cells critical for glomerular filtration, and leads to proteinuria and kidney failure. Inherited forms of FSGS are caused by Rac1-activating mutations, and Rac1 induces TRPC5 ion channel activity and cytoskeletal remodeling in podocytes. Whether TRPC5 activity mediates FSGS onset and progression is unknown. We identified a small molecule, AC1903, that specifically blocks TRPC5 channel activity in glomeruli of proteinuric rats. Chronic administration of AC1903 suppressed severe proteinuria and prevented podocyte loss in a transgenic rat model of FSGS. AC1903 also provided therapeutic benefit in a rat model of hypertensive proteinuric kidney disease. These data indicate that TRPC5 activity drives disease and that TRPC5 inhibitors may be valuable for the treatment of progressive kidney diseases.

A previous genetic analysis comparing the Dahl salt-sensitive (S) rat to the spontaneously hypertensive rat (SHR) identified a major locus on chromosome 2 that influences proteinuria in the S rat. In the present study, blood pressure, proteinuria, and renal hemodynamics were evaluated in congenic strains with small segments of the protective SHR genome on the S background. Proteinuria and renal function were significantly improved in the congenic strains compared to the S. The causative locus interval was narrowed to <375 kb based on congenic strains, haplotype data, comparative mapping, and concordance with human genetic studies. Sequencing of the coding region of genes in this region identified 36 SNPs (13 nonsynonymous and 23 synonymous). Gene expression profiling indicated that only few genes exhibited differential expression. Arhgef11, Pear1, and Sh2d2 were identified as important candidate genes that may be linked to kidney injury in the S rat. In particular, Arhgef11 plays an important role in the activation of the Rho-ROCK signaling pathway. Inhibition of this pathway using fasudil resulted in a significant reduction of proteinuria in treated S rats (compared to untreated S). However, no difference was observed between treated or untreated SHR or congenic strains. The homologous region in humans was found to be associated with estimated glomerular filtration rate (eGFR) in the Candidate Gene Association Resource (CARe) population. In summary, these findings demonstrate that allelic variants in Arhgef11, acting through the Rho-ROCK pathway, could influence kidney injury in the S as well as provide insight into human kidney disease.

The current study examined the effect of obesity on the development of renal injury within the genetic background of the Dahl salt-sensitive rat with a dysfunctional leptin receptor derived from zinc-finger nucleases (SSmutant strain). At 6 wk of age, body weight was 35% higher in the SSmutant strain compared with SS rats and remained elevated throughout the entire study. The SSmutant strain exhibited impaired glucose tolerance and increased plasma insulin levels at 6 wk of age, suggesting insulin resistance while SS rats did not. However, blood glucose levels were normal throughout the course of the study. Systolic arterial pressure (SAP) was similar between the two strains from 6 to 10 wk of age. However, by 18 wk of age, the development of hypertension was more severe in the SSmutant strain compared with SS rats (201 ± 10 vs. 155 ± 3 mmHg, respectively). Interestingly, proteinuria was substantially higher at 6 wk of age in the SSmutant strain vs. SS rats (241 ± 27 vs. 24 ± 2 mg/day, respectively) and remained elevated until the end of the study. The kidneys from the SSmutant strain displayed significant glomerular injury, including podocyte foot process effacement and lipid droplets compared with SS rats as early as 6 wk of age. By 18 wk of age, plasma creatinine levels were twofold higher in the SSmutant strain vs. SS rats, suggesting the presence of chronic kidney disease (CKD). Overall, these results indicate that the SSmutant strain develops podocyte injury and proteinuria independently of hyperglycemia and elevated arterial pressure that later progresses to CKD.

Nuclear hormone receptors of the NR4A subgroup have been implicated in cancer, atherosclerosis, and metabolic disease. However, little is known about the role of these receptors in kidney health or disease. Nr4a1-deficient rats (Nr4a1 The incidence of CKD has increased over the last 2 decades. 1 Current estimates suggest that approximately 10% of adults in the United States have CKD. 2 Considering only federal Medicare spending, the direct economic effect of CKD is staggering. The cost to treat CKD (predialysis) in 2010 was $41 billion, in addition to ESRD (dialysis and transplantation) costs estimated at $32.9 billion. 3 A significant problem is that current treatment options are not ideal and only serve to slow the progression of CKD. Thus, the identification of genes and/or biologic pathways that mediate progressive kidney disease is critical to both developing new and/or improved treatments for CKD and curbing the associated financial burden. Nuclear hormone receptors are transcription factors that play a role in a variety of biologic processes and are induced in multiple tissues by diverse stimuli, such as b-adrenoceptor agonists, cold, fatty acids, glucose, insulin, and cholesterol. 4 The nuclear receptor (NR) 4A subgroup of nuclear hormone receptors is composed of three members: Nr4a1 (Nur77), Nr4a2 (Nurr1), and Nr4a3 (Nor1). In contrast with other NRs, the activity of NR4A receptor family is ligand independent and regulated at the level of gene expression and protein stability. 5 The NR4A subgroup has been linked to cancer, 6