Genetic deficiency of Smad3 protects against murine ischemic acute kidney injury

Abstract

TGF-β1 contributes to chronic kidney disease, at least in part, via Smad3. TGF-β1 is induced in the kidney following acute ischemia, and there is increasing evidence that TGF-β1 may protect against acute kidney injury. As there is a paucity of information regarding the functional significance of Smad3 in acute kidney injury, the present study explored this issue in a murine model of ischemic acute kidney injury in Smad3+/+ and Smad3−/− mice. We demonstrate that, at 24 h after ischemia, Smad3 is significantly induced in Smad3+/+ mice, whereas Smad3−/− mice fail to express this protein in the kidney in either the sham or postischemic groups. Compared with Smad3+/+ mice, and 24 h following ischemia, Smad3−/− mice exhibited greater preservation of renal function as measured by blood urea nitrogen (BUN) and serum creatinine; less histological injury assessed by both semiquantitative and qualitative analyses; markedly suppressed renal expression of IL-6 and endothelin-1 mRNA (but comparable expression of MCP-1, TNF-α, and heme oxygenase-1 mRNA); and no increase in plasma IL-6 levels, the latter increasing approximately sixfold in postischemic Smad3+/+ mice. We conclude that genetic deficiency of Smad3 confers structural and functional protection against acute ischemic injury to the kidney. We speculate that these effects may be mediated through suppression of IL-6 production. Finally, we suggest that upregulation of Smad3 after an ischemic insult may contribute to the increased risk for chronic kidney disease that occurs after acute renal ischemia.

Genetic deficiency of Smad3 protects the kidneys from atrophy and interstitial fibrosis in 2K1C hypertension

“…The blunted TGF-␤1 response in the stenotic kidney of Smad3 KO mice is consistent with our recent studies demonstrating that the induction of TGF-␤1 following acute occlusive ischemia to the kidney is blunted in Smad3 KO mice (44). Thus, in the stressed kidney, but not the unstressed kidney, there is a positive feedback loop between Smad3 and TGF-␤1, the basis for which may reside in the presence of Smad3 binding sites in the TGF-␤1 gene promoter.…”

“…Studies were conducted using male and female littermate Smad3 KO and WT mice at ϳ15-20 wk of age. We have recently employed these mutant mice in studies of ischemic acute kidney injury (44). All animal procedures were performed in accordance with National Institutes of Health Guide for the Care and Use of Laboratory Animals and approved by the Mayo Clinic Institutional Animal Care and Use Committee.…”

Deleting the TGF-β Receptor Attenuates Acute Proximal Tubule Injury

“…Our finding that deleting TbRII is renoprotective is consistent with the attenuated increase in serum creatinine and BUN observed in injured Smad3 2/2 mice. 21 In contrast to these genetic approaches, blocking TGF-b activity with chemical inhibitors did not show a significant effect on renal function after AKI. 16,20 Genetic techniques may allow more thorough inhibition of TGF-b activity that is sustained over time, while an inhibitor is generally given at the time of injury and thus lacks the effects of chronic inhibition.…”

“…18,19 In contrast to these studies, the use of a neutralizing pan-TGF-b antibody did not significantly alter the acute response to ischemia/reperfusion, 20 and TGF-b signaling was shown to have detrimental effects on the response to AKI because a TGF-b type I receptor inhibitor (ALK5) accelerated recovery and Smad3 2/2 mice had greater preservation of renal function and less histologic injury after ischemia/reperfusion injury. 16,21 With such varied conclusions, TGF-b's role in AKI remains unclear. Furthermore, these in vivo studies used chemical inhibitors or genetic techniques to systemically inhibit TGF-b activity, an approach that does not elucidate the role of TGF-b signaling specifically in the proximal tubule.…”

PTEN loss defines a TGF-β-induced tubule phenotype of failed differentiation and JNK signaling during renal fibrosis

“…These abnormalities may be interconnected; and TGF-␤ may be a proximal trigger. TGF-␤, its receptors, and Smad signaling are increased in tubules proliferating after ischemia, suggesting an autocrine signaling loop (14,31,37). TGF-␤ antibodies ameliorated the TIF that developed after AKI consistent with a role for the cytokine in fibroblast activation (37).…”