Kidney Injury Accelerates Cystogenesis via Pathways Modulated by Heme Oxygenase and Complement

Abstract

AKI accelerates cystogenesis. Because cystogenic mutations induce strong transcriptional responses similar to those seen after AKI, these responses may accelerate the progression of cystic renal disease. Here, we modulated the severity of the AKI-like response in Cys1 cpk/cpk mice, a model that mimics autosomal recessive polycystic kidney disease. Specifically, we induced or inhibited activity of the renoprotective enzyme heme oxygenase (HO) and determined the effects on renal cystogenesis. We found that induction of HO attenuated both renal injury and the rate of cystogenesis, whereas inhibition of HO promoted cystogenesis. HO activity mediated the response of NFkB, which is a hallmark transcriptional feature common to both cystogenesis and AKI. Among the HO-modulated effects we measured, expression of complement component 3 (C3) strongly correlated with cystogenesis, a functionally relevant association as suggested by Cys1 cpk/cpk mice with genetically induced C3 deficiency. Because both C3 deficiency and HO induction reduce cyst number and cyst areas, these two factors define an injury-stimulated cystogenic pathway that may provide therapeutic targets to slow the formation of new renal cysts and the growth of existing cysts.

Complement C3 activation in cyst fluid and urine from autosomal dominant polycystic kidney disease patients

“…These data are consistent with our earlier observation of a cystic disease progression-inhibiting effect of genetically induced C3 deficiency on autosomal recessive polycystic kidney disease (ARPKD) in the Cys1 cpk mouse model [2], and with the known association of C3-activity altering gene polymorphisms with renal function decline amongst patients with ADPKD [3]. Consistent with the opinion expressed by Su et al [1], we attributed the renal cystogenesis-promoting effects of complement to its intrarenal dysregulation [2,4]. We supported this hypothesis by documenting transcriptional dysregulation for genes encoding multiple complement proteins within kidneys with rapidly vs slowly progressing cystic disease [4].…”

Genomic instability in patients with autosomal-dominant polycystic kidney disease

“…Numerous models have been proposed to account for the development of cysts. [20][21][22] Zheleznova et al 23 suggested that epidermal growth factor receptor-mediated interactions are key elements in renal tubular cell proliferation, not only in the normal kidney, but also under conditions of cyst formation and enlargement. Activation of the intrinsic kinase domain results in phosphorylation of specific tyrosine residues, which in turn leads to the activation of intracellular signalling pathways.…”

Complement activation in progressive renal disease

“…In mouse models of cystic kidney disease there is increased expression of complement genes in cyst epithelium, particularly C3, and also evidence of complement activation [57,58] . To investigate a role for complement in cystogenesis Cys1 cpk/cpk polycystic kidney disease mice were crossed with C3 deficient mice which lack the main effector functions of complement [58] . Mice deficient in C3 deve loped fewer cysts and had reduced renal volume, suggesting that complement, possibly by modifying inflammation, has a role in cyst development.…”

“…It is evident that inflammatory and fibrotic changes occur in renal tissue surrounding the cyst and this may in part be responsible for the loss of renal function that occurs. In mouse models of cystic kidney disease there is increased expression of complement genes in cyst epithelium, particularly C3, and also evidence of complement activation [57,58] . To investigate a role for complement in cystogenesis Cys1 cpk/cpk polycystic kidney disease mice were crossed with C3 deficient mice which lack the main effector functions of complement [58] .…”